GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models

Yi Na Dong Emily McMillian Elisia M Clark Hong Lin David R Lynch, Human Molecular Genetics, ddy448, doi:10.1093/hmg/ddy448 Published: 26 December 2018

We present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in HEK293 cells while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two GAA repeat expansions and compound heterozygous patients with point mutations.

Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures

Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M. Gottesfeld, and Elisabetta Soragni; J. Biol. Chem. jbc.RA118.006515. doi:10.1074/jbc.RA118.006515

How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using “scarless” gene-editing methods, we created isogenic iPSC lines that differ only in the length of the GAA•TTC repeats. To uncover the gene expression signatures due to the GAA•TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. We found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.

Correction of half the cardiomyocytes fully rescue Friedreich Ataxia mitochondrial cardiomyopathy through cell-autonomous mechanisms

Brahim Belbellaa, Laurence Reutenauer, Laurent Monassier, Hélène Puccio; Human Molecular Genetics, , ddy427, doi:10.1093/hmg/ddy427

Correlative analysis of vector cardiac biodistribution, survival, cardiac function and biochemical hallmarks of the disease revealed that full rescue of the cardiac function was achieved when only half of the cardiomyocytes were transduced. In addition, meaningful therapeutic effect was achieved with as little as 30% transduction coverage. This therapeutic effect was mediated through cell-autonomous mechanisms for mitochondria homeostasis, although a significant increase in survival of uncorrected neighboring cells was observed.

Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom

Gabrielle Norrish Ella Field Karen Mcleod Maria Ilina Graham Stuart Vinay Bhole Orhan Uzun Elspeth Brown Piers E F Daubeney Amrit Lota Katie Linter Sujeev Mathur Tara Bharucha Khoon Li Kok Satish Adwani Caroline B Jones Zdenka Reinhardt Juan Pablo Kaski. European Heart Journal, ehy798, doi:10.1093/eurheartj/ehy798

Six hundred and eighty-seven patients with HCM presented at a median age of 5.2 years (range 0–16). Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich’s ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001). In those with familial disease, median age of presentation was higher (11 years vs. 6 years, P < 0.0001), 141 (58%) presente

Be open about drug failures to speed up research

Enrica Alteri and Lorenzo Guizzaro. Nature 563, 317-319 (2018) doi: 10.1038/d41586-018-07352-7

COMMENT 13 NOVEMBER 2018

Access to evidence from disappointing drug-development programmes advances the whole scientific process, explain Enrica Alteri and Lorenzo Guizzaro.
To speed up progress, companies must be more forthcoming with their data and thinking, and regulators must find ways to help them with this. The ultimate goal is to allow broader access to data from drug-development programmes and to enable faster learning by the entire research community.
We hope that this project (Alzheimer’s treatments) leads to similar efforts in other diseases that are difficult to treat. We owe it to the public and to patients to ensure that R&D efforts continue to move towards greater transparency.

From scientific discovery to treatments for rare diseases – the view from the National Center for Advancing Translational Sciences – Office of Rare Diseases Research

Petra Kaufmann, Anne R. Pariser and Christopher Austin. Orphanet Journal of Rare Diseases 2018 13:196 doi:10.1186/s13023-018-0936-x

We now live in a time of unprecedented opportunities to turn scientific discoveries into better treatments for the estimated 30 million people in the US living with rare diseases. Despite these scientific advances, more than 90% of rare diseases still lack an effective treatment. New data and genetics technologies have resulted in the first transformational new treatments for a handful of rare diseases. This challenges us as a society to accelerate progress so that no disease and no patient is, ultimately, left behind in getting access to safe and effective therapeutics.

Large Interruptions of GAA Repeat Expansion Mutations in Friedreich Ataxia Are Very Rare

Al-Mahdawi Sahar, Ging Heather, Bayot Aurelien, Cavalcanti Francesca, La Cognata Valentina, Cavallaro Sebastiano, Giunti Paola, Pook Mark A. Front Cell Neurosci. 2018 Nov 21;12:443. doi: 10.3389/fncel.2018.00443. eCollection 2018.

Friedreich ataxia is a multi-system autosomal recessive inherited disorder primarily caused by homozygous GAA repeat expansion mutations within intron 1 of the frataxin gene. The resulting deficiency of frataxin protein leads to progressive mitochondrial dysfunction, oxidative stress and cell death, with the main affected sites being the large sensory neurons of the dorsal root ganglia and the dentate nucleus of the cerebellum. The GAA repeat expansions may be pure (GAA)n in sequence or may be interrupted with regions of non-GAA sequence. To our knowledge there has been no large-scale study of FRDA patient DNA samples to determine the frequency of large interruptions in GAA repeat expansions. Therefore, we have investigated a panel of 245 Friedreich ataxia patient and carrier DNA samples using GAA repeat PCR amplification and MboII restriction enzyme digestion. We demonstrate that the vast majority (97.8%) of Friedreich ataxia GAA repeat expansion samples do not contain significant sequence changes that would result in abnormal MboII digestion profiles, indicating that they are primarily pure GAA repeats. These results show for the first time that large interruptions in the GAA repeats are very rare.

Ataxia with isolated vitamin E deficiency presenting as mutation negative Friedreich’s ataxia

Hammans SR, Kennedy CR. Journal of Neurology, Neurosurgery & Psychiatry 1998;64:368-370. doi:10.1136/jnnp.64.3.368

Ataxia with vitamin E deficiency is an autosomal recessive condition associated with a defect in the α-tocopherol transfer protein. Clinically it manifests as a progressive ataxia with a phenotype resembling that of Friedreich’s ataxia.

Case report: A 16 year old girl was referred with a previous clinical diagnosis of Friedreich’s ataxia.

We suggest that all patients with progressive ataxia of unknown cause should have vitamin E assayed. This should be performed with frataxin studies in patients in whom the diagnosis of Friedreich’s ataxia is considered. Further, any patient with a clinical diagnosis of Friedreich’s ataxia with negative mutation analysis should have vitamin E measured.

Trends in robot-assisted and virtual reality-assisted neuromuscular therapy: a systematic review of health-related multiplayer games

Kilian Baur, Alexandra Schättin, Eling D. de Bruin, Robert Riener, Jaime E. Duarte and Peter Wolf. Journal of NeuroEngineering and Rehabilitation 2018 15:107 doi:10.1186/s12984-018-0449-9

Multiplayer modes can enhance the players’ perceived game experience and positively influence the players’ performance. Based on the small number of relevant studies published so far, a conclusion cannot yet be drawn about which multiplayer mode is best during neurorehabilitation training. A meta-analysis of game experience and game performance outcomes may be suggested as soon as more multiplayer studies with homogeneous outcome measures will be published. Nevertheless, this review demonstrated that the players’ individual skill levels and personalities, as well as their role in the game, must be taken into account when selecting and designing multiplayer modes.

Based on the model of flow and the challenge point framework, we suggest an individual adaptation of game conditions, i.e. conditional task difficulty, to assimilate differently skilled players for an optimal game experience. Furthermore, player specific selection of multiplayer modes may result in more robust interventions regarding game experience and requires less assimilation of differently skilled players.

We suggest breaking the limited variety in multiplayer modes and fully exploring multiplayer modes and co-player’s characteristics such as the co-players presence, skill level, personality and relation to the player. We further suggest that future studies use a more stringent research design in which participants are allocated to either single play or multiplayer modes of exercise through randomised assignment.

Federating patients identities: the case of rare diseases

Meriem Maaroufi, Paul Landais, Claude Messiaen, Marie-Christine Jaulent and Rémy Choquet; Orphanet Journal of Rare Diseases 2018 13:199 doi:10.1186/s13023-018-0948-6

Patient information in rare disease registries is generally collected from numerous data sources, necessitating the data to be federated. In addition, data for research purposes must be de-identified. Transforming nominative data into de-identified data is thus a key issue, while minimizing the number of identity duplicates. We propose a method enabling patient identity federation and rare disease data de-identification while preserving the pertinence of the provided data.
The simplicity of the algorithm and the universal and stable characteristics of the required input data make it potentially applicable beyond its current scope of implementation including European cross-border RD projects in the light of the recent EU Global Regulation for Data Protection.

Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia (NICOFA)

A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia. ClinicalTrials.gov Identifier: NCT03761511, First Posted: December 3, 2018

Friedreich ataxia is the most frequent early-onset autosomal recessive hereditary ataxia. It is caused by a pathological expansion of a GAA repeat in the first intron of the frataxin gene (FXN) and results in decreased levels of FXN protein. FXN deficiency results in a relentlessly progressive neurodegenerative condition which frequently presents around puberty. Patients gradually lose coordination, become dysarthric and are frequently wheel-chair bound as adolescents. There is no disease modifying therapy and many patients die prematurely of cardiomyopathy. It was subsequently found that the FXN gene is silenced at the chromatin level by the formation of heterochromatin and that this heterochromatin formation can be antagonized by histone deacetylase inhibitors (HDACi) (Chan et al., 2013). A recent proof-of-concept clinical study on ten patients with Friedreich ataxia demonstrated that FXN levels can be restored to those seen in asymptomatic carriers using the class III HDACi nicotinamide at a dose that is well tolerated by patients (Libri et al., 2014). Since carriers are asymptomatic, this degree of restoration of FXN expression might be expected to halt disease progression. Nicotinamide readily crosses the blood brain barrier and has previously been given at high doses for long periods to normal individuals without serious adverse effects (Gale et al., 2004; Knip et al., 2000). This study will be the first to provide clinical

Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 225 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia
Estimated Study Start Date : December 2018
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020

Patients must be ≥18 years old and have a weight of at least 50kg.

The POWER-tool: Recommendations for involving patient representatives in choosing relevant outcome measures during rare disease clinical trial design

C.M.W. Gaasterland, M.C. Jansen-van der Weide, E. Vroom, K. Leeson-Beevers, M. Kaatee, R. Kaczmarek, B. Bartels, W.L. van der Pol, K.C.B. Roes, J.H. van der Lee, Health Policy, 2018, ISSN 0168-8510, doi:10.1016/j.healthpol.2018.09.011.

In clinical trials, it is relevant to ask patients and/or their caregivers which aspects concerning their disease they consider important to measure when a new intervention is being investigated. Those aspects, useful as outcome measures in a trial, are of pivotal importance for the result of the trial and the subsequent decision-making. In rare diseases the choice of outcome measures may be even more important, due to the small numbers and heterogeneity of the patients that are included.

We have developed a tool to involve patients in the determination of outcome measures and the choice of measurement instruments. This tool was developed together with a patient think tank, consisting of a group of rare disease patient representatives, and by interviewing end users. We have road-tested our tool in an ongoing trial, and evaluated it during a focus group meeting.

The tool consists of three steps: 1) Preparation, 2) Consultation of patients, 3) Follow-up during which the consultation results are implemented in the trial design.

The tool provides guidelines for researchers to include the patient’s opinion in the choice of outcome measures in the trial design stage. We describe the development of the POWER-tool (Patient participation in Outcome measure WEighing for Rare diseases), and first experiences of the tool in an ongoing trial.

Impact of biobanks on research outcomes in rare diseases: a systematic review

Monique Garcia, Jenny Downs, Alyce Russell and Wei Wang; Orphanet Journal of Rare Diseases 2018 13:202 doi:10.1186/s13023-018-0942-z

Alleviating the burden of rare diseases requires research into new diagnostic and therapeutic strategies. We undertook a systematic review to identify and compare the impact of stand-alone registries, registries with biobanks, and rare disease biobanks on research outcomes in rare diseases.

A list of the registries, and their association with BBs at the time the original article was published, can be found in this paper. There were, however, small RDBBs that had collected only 50 samples (such as the Friedrich’s Ataxia fibroblast repository). Li et al. reported that smaller RDBBs have their advantages over larger RDBB networks in the sense that they can focus on a single diseases or syndromes, or group of diseases, and can successfully accumulate significant numbers of cell lines, whilst developing an intimate understanding of the disease

OGTT is recommended for glucose homeostasis assessments in Friedreich ataxia

Azzi, A. , Cosentino, C. , Kibanda, J. , Féry, F. and Cnop, M. (2018). Ann Clin Transl Neurol. doi:10.1002/acn3.686

Diabetes is a common complication of Friedreich ataxia, requiring sensitive diagnostic methods. Here, we compared the performance of different tests that assess glucose tolerance, insulin sensitivity, and β‐cell function in Friedreich ataxia patients, heterozygous FXN mutation carriers and controls. We find that diabetes is underdiagnosed with fasting glucose alone. The oral glucose tolerance test (OGTT) provides 1.2‐ to 3.5‐fold more diagnoses of impaired glucose homeostasis and diabetes, and adequately measures insulin sensitivity, insulin secretion, and β‐cell function. Clinicians in charge of Friedreich ataxia patients and researchers should incorporate the OGTT as an accurate diagnostic and research tool.

Mining Facebook Data of People with Rare Diseases: A Content-Based and Temporal Analysis

Subirats L, Reguera N, Bañón AM, Gómez-Zúñiga B, Minguillón J, Armayones M.; Int J Environ Res Public Health. 2018;15(9):1877. Published 2018 Aug 30. doi:10.3390/ijerph15091877

This research characterized how Facebook deals with rare diseases. This characterization included a content-based and temporal analysis, and its purpose was to help users interested in rare diseases to maximize the engagement of their posts and to help rare diseases organizations to align their priorities with the interests expressed in social networks. This research used Netvizz to download Facebook data, word clouds in R for text mining, a log-likelihood measure in R to compare texts and TextBlob Python library for sentiment analysis. The Facebook analysis shows that posts with photos and positive comments have the highest engagement. We also observed that words related to diseases, attention, disability and services have a lot of presence in the decalogue of priorities (which serves for all associations to work on the same objectives and provides the lines of action to be followed by political decision makers) and little on Facebook, and words of gratitude are more present on Facebook than in the decalogue. Finally, the temporal analysis shows that there is a high variation between the polarity average and the hour of the day.

Real‐time use of audio‐biofeedback can improve postural sway in patients with degenerative ataxia

Zofia Fleszar, Sabato Mellone, Martin Giese, Carlo Tacconi, Clemens Becker, Ludger Schöls, Matthis Synofzik, Winfried Ilg; Annals of Clinical and Translational Neurology, Early View, First published: 28 November 2018 doi:10.1002/acn3.699

Our findings provide proof‐of‐principle evidence that subjects with cerebellar degeneration are still able to integrate additional sensory modalities to compensate for deficient postural control: They can use auditory cues functionally similar to vision in the absence of vision, and additive to vision in the presence of vision (in case of pronounced postural sway). These findings might inform future assistive strategies for cerebellar ataxia

Mitochondria, Nrf2 and mTOR

Gino Cortopassi. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S7, doi:10.1016/j.freeradbiomed.2018.10.382.

Abstract: Friedreich's ataxia (FA) is the most common recessive ataxia, and it's phenotype is clinically indistinguishable from AVED, a deficiency of Vitamin E transport. We were the first to show that Friedreich's patient cells are very sensitive to oxidative stress. Ultimately this defect appears to reside in a deficiency of the antioxidant pathway Nrf2, which is less active in Friedreich's patient cells, and in FA animal models. Perhaps as a result of this Nrf2 defect, there is increased inflammation in Friedreich's patient cells and mice. But as Nrf2 is not only important in antioxidant homeostasis, but also mitochondrial homeostasis, this was investigated in Friedreich's models and patients. We found that Friedreich's cells, mice, and even people have an approximately 40% mitochondrial biogenesis defect. A high-throughput screening campaign for drugs that rescued Friedreich's cells from death identified three Nrf2 inducers, which could be of benefit in human Friedreich's therapy. One of these drugs, dimethyl fumarate, was shown to dose-dependently increase mitochondrial biogenesis and function when dosed in cells, and to increase mitochondrial biogenesis in mouse and human tissues, with a mechanism that appears to require Nrf2. Thus there is an interplay between Nrf2, mitochondrial biogenesis, and antioxidant status. We observed in a particular cancer there are alterations of mitochondrial biogenesis, which appear to result from differential Nrf2 activity. These differences in mitochondrial number allow the selective killing of such cells by mitochondrial inhibitors and a novel category of mTOR inhibitors.

Heme oxygenase-1 is required for iron homeostasis and mitochondrial respiration

Jennifer Carr, Ping La, Phyllis Dennery. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S81, doi.org/10.1016/j.freeradbiomed.2018.10.182.

Heme is an essential cofactor in several enzymes of the electron transport chain (ETC) where its primary function is the coordination of iron to facilitate redox reactions. Unbound, free heme is strongly oxidative such that the cell has evolved mechanisms to prevent it from causing oxidative damage. This includes the catalytic breakdown of heme by heme oxygenase (HO-1), generating antioxidants CO and biliverdin. However the catabolism of heme also releases highly toxic free iron which seems counter productive to the antioxidant effort. We sought to explore the role of HO-1 in iron homeostasis using HO-1 knockout mouse embryonic fibroblasts and HO-1 deficient human liver cells. By Western blot these cells showed dysregulated iron handling including increased expression of transferrin receptor and decreased expression of ferritin and ferroportin compared to wild type controls. Additionally cytosolic aconitase activity was decreased in HO-1 deficient cells while the mutually exclusive mRNA binding activity of aconitase was increased. This switch is indicative of reduced FeS cluster availability. Consistent with FeS cluster deficiency we observed decreased frataxin mRNA levels, the product of which is involved in FeS cluster assembly in the mitochondria. Because FeS clusters are important in the ETC we examined mitochondrial respiration with a Seahorse Bioanalyzer (Agilent) and found it to be markedly reduced in HO-1 knockout cells. Interestingly, this was partially rescued by exogenous iron (1nM transferrin). Our findings suggest that an additional and important role of HO-1 is the maintenance of cellular iron homeostasis via the release of iron upon breakdown of heme.

Corporate Social Responsibility (CSR) of Innovative Pharmaceutical Corporations. The Case of BIOGEN

Janina Witkowska. Comparative Economic Research, Volume 21: Issue 3 45–62, First Online: 19 Sep 2018 DOI:10.2478/cer-2018-0018

The aim of a paper published in Comparative Economic Research was to discuss the common features and specificity of Corporate Social Responsibility (CSR) practices of innovative transnational corporations acting in the pharmaceutical industry, understood as their ability to make a breakthrough in the treatment of rare, incurable diseases. Traditional CSR practices include corporate philanthropy, community and neighbourhood programmes, volunteerism, etc. The author of the paper argues that the issue of CSR in the innovative pharmaceutical industry is the pricing of orphan and ultra-orphan drugs, while the case study of BIOGEN seems to show that the company is aware of the need to remove barriers to access the medicines. The author also suggests that a stronger international cooperation is needed to ensure equity of medicine access in a more efficient way.

Depression disorder in patients with cerebellar damage: Awareness of the mood state

ilvia Clausi, Michela Lupo, Giusy Olivito, Libera Siciliano, Maria Pia Contento, Fabio Aloise, Luigi Pizzamiglio, Marco Molinari, Maria Leggio. Journal of Affective Disorders, Volume 245, 2019, Pages 386-393, doi:10.1016/j.jad.2018.11.029.

Cerebellar dysfunction might slow the data integration necessary for mood state awareness, resulting in difficulty of depressed CB patients in explicitly recognizing their mood “in the here and now”.
In conclusion, cerebellar involvement in the conscious component of emotional behaviour, related to awareness of one's affective state and interpretation of one's mood, may contribute to a loss of the‘online’ self-perception of negative mood that characterizes depressive disorders in the presence of cerebellar pathology. These data may help explain why depression in cerebellar patients is often underdiagnosed.

Paradoxical disruption of Nrf2 signaling despite mitochondrial iron driven oxidative stress in Friedreich’s ataxia cardiomyopathy

Michael Huang, Amy Anzovino, Shannon Chiang, Bronwyn Brown, Clare Hawkins, Des Richardson. Free Radical Biology and Medicine, Volume 128, Supplement 1, 2018, Page S131, doi.org/10.1016/j.freeradbiomed.2018.10.346

Cardiomyopathy is the leading cause of mortality for the most prevalent inherited ataxia, Friedreich’s ataxia (FA). Deficient expression of the mitochondrial protein frataxin that is crucial for mitochondrial iron metabolism is the cause of FA, which exhibits marked mitochondrial Fe accumulation. Our studies using a conditional cardiac frataxin knockout (KO) mouse that mirrors FA cardiomyopathy have shown frataxin deletion leads to pronounced trafficking of cardiac iron from the cytosol to the mitochondrion, leading to a cytosolic iron-deficiency and mitochondrial iron accumulation in the form of non-protein-bound, biomineral iron aggregates. The ensuing oxidative stress is likely a key contributor to FA pathology. The transcription factor, nuclear factor E2-related factor 2 (Nrf2), is the master regulator of cellular antioxidant response. In the frataxin KO mouse, our studies demonstrated increased protein and GSH oxidation in the KO relative to wild-type (WT) littermates. Despite this, we found paradoxical decreases in total and nuclear Nrf2 protein and an increase in its inhibitor, Keap1, which mediates Nrf2 degradation in the cytosol. Moreover, a mechanism involving activation of the nuclear Nrf2 export/degradation machinery via Gsk3β-signaling was found in the KO heart. This is evident by: (i) increased Gsk3β activation; (ii) increased Fyn-mediated nuclear Nrf2 export; and (iii) increased expression of β-TrCP that is involved in Nrf2 degradation. Furthermore, a corresponding decrease in Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA was observed in KO heart. Collectively, despite marked mitochondrial iron accumulation in FA cardiomyopathy, Nrf2 activity was disrupt via two mechanisms: increased Keap1 that decreases cytosolic Nrf2, and the activation of Gsk3β-signaling that decreases nuclear Nrf2.

Del deseo a la realidad: la edición genética (aún) no está preparada para tratar a pacientes

SINC, la ciencia es noticia (17 noviembre 2018). Lluís Montoliu, es investigador científico del Centro Nacional de Biotecnología (CNB-CSIC) y Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER-ISCIII), además de miembro del Comité de Ética del CSIC.

Las terapias génicas basadas en CRISPR para curar enfermedades todavía tardarán en llegar. Quizás no sea este el titular que quisiéramos leer, pero es el mensaje que hay que repetir para no generar falsas expectativas sobre esta potente herramienta de corta-pega genético.

Hoy en día se están desarrollando múltiples variantes de la técnica CRISPR, a cual más innovadora e imaginativa. Algunas de ellas son extremadamente prometedoras, como los editores de bases, una evolución de las herramientas CRISPR capaz de cambiar nucleótidos concretos del genoma sin necesidad de cortarlo. Pero todas ellas conllevan todavía riesgos inaceptables, tanto en seguridad como en eficacia, para saltar al hospital.

Son métodos sofisticados que nos permiten abordar experimentos en el laboratorio como nunca antes habíamos podido hacerlo, pero que todavía no pueden trasladarse a la clínica. Necesitan de mucho más trabajo, mucha más investigación en el laboratorio.

Mitochondrial calcium signalling and neurodegenerative diseases

Elena Britti, Fabien Delaspre, Jordi Tamarit, Joaquim Ros; Neuronal Signaling Dec 2018, 2 (4) NS20180061; DOI: 10.1042/NS20180061

Mitochondrial calcium homoeostasis clearly contributes to cellular fitness and survival. Maintenance of accurate calcium levels is highly regulated by mitochondrial proteins that are connected, either directly or via other proteins, to ER calcium stores. As described in this review, prior to cell death, mitochondrial calcium deregulation could be the consequence of increased influx (MCU complex), or decreased efflux (Na+/Ca2+ exchanger) or altered capacity for calcium buffering caused by mitochondrial damage, such as MPTP opening. Calcium deregulation would then lead to several neurodegenerative processes that resulted in cell death. Thus, identifying specific targets to maintain calcium balance and mitochondrial function appears to be of paramount importance in preventing, alleviating or even curing neurodegenerative diseases.
Although the initial steps of the process through which decreased levels of frataxin leads to neurodegeneration are still unknown, the above-reported findings clearly point to an important role of calcium deregulation in the pathophysiology of FA. Therapeutic strategies that impact on the proteins responsible for calcium overload and its consequences could be of great value for developing a cure for the disease.

FAST-1 antisense RNA epigenetically alters FXN expression

Hajar Mikaeili, Madhavi Sandi, Aurélien Bayot, Sahar Al-Mahdawi & Mark A. Pook; Scientific Reports, volume 8, Article number: 17217 (2018). doi:10.1038/s41598-018-35639-2

Our results show that knocking down FAST-1 in FRDA fibroblast cells increases FXN gene expression (Fig. 10). Therefore, it can be concluded that, since FAST-1 is associated with epigenetic repression of the FXN gene, inhibition of FAST-1 may be an approach to increase the FXN transcripts and stimulate subsequent protein expression. Indeed, our results demonstrate that knocking down FAST-1 in FRDA results in a significant increase in aconitase enzyme activity, a good indicator of frataxin function within cells. Our data suggest that since FAST-1 is associated with FXN gene silencing, inhibition of FAST-1 may be an approach for FRDA therapy. Considering the nature of NATs and the fact that many currently available drugs would not affect the activity of non-coding RNA molecules, developing new methods to disrupt the function of NATs seems necessary.

NMR as a Tool to Investigate the Processes of Mitochondrial and Cytosolic Iron-Sulfur Cluster Biosynthesis

Cai, K.; Markley, J.L.; Molecules 2018, 23, 2213. doi:10.3390/molecules23092213

Defects in protein components of the mitochondrial ISC machinery are associated with numerous diseases, including Friedreich ataxia (defects in frataxin), myopathy (defects in ISCU or FDX2), and multiple mitochondrial dysfunction syndromes (defects in NFU1, BOLA3, ISCA2, and IBA57). Extensive investigations over the past two decades have identified many new components and established key steps in the ISC machinery. A growing number of diseases associated with ISC defects are being discovered through clinical, genetic, and biochemical studies.

Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes

Lili Guo, Qingqing Wang, Liwei Weng, Lauren A. Hauser, Cassandra J. Strawser, Clementina Mesaros, David R. Lynch & Ian A. Blair; Scientific Reports volume 8, Article number:17043 (2018) DOI:10.1038/s41598-018-35346-y

The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich’s ataxia and monitor the efficacy of therapeutic interventions.

Emerging and Dynamic Biomedical Uses of Ferritin

Brian Chiou and James R. Connor; Pharmaceuticals 2018, 11(4), 124; doi:10.3390/ph11040124

Review

One interesting new development has been proposed in Friedreich’s Ataxia where the authors discuss the hypothesis that the mitochondrial protein frataxin may oligomerize like ferritin and perform functions redundant with mitochondrial ferritin, acting as another iron storage molecule. Loss of frataxin and this iron storage property may result in Friedreich’s Ataxia and subsequent neurodegeneration.

Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties

Caridad Pontes, Juan Manuel Fontanet, Roser Vives, Aranzazu Sancho, Mònica Gómez-Valent, José Ríos, Rosa Morros, Jorge Martinalbo, Martin Posch, Armin Koch, Kit Roes, Katrien Oude Rengerink, Josep Torrent-Farnell and Ferran Torres; Orphanet Journal of Rare Diseases 2018 13:206 doi:10.1186/s13023-018-0926-z

The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base.

Plasma Markers of Neurodegeneration Are Raised in Friedreich’s Ataxia

Zeitlberger Anna M., Thomas-Black Gilbert, Garcia-Moreno Hector, Foiani Martha, Heslegrave Amanda J., Zetterberg Henrik, Giunti Paola; Frontiers in Cellular Neuroscience 2018, 12 366, DOI=10.3389/fncel.2018.00366

This study provides the first assessment of plasma markers of neurodegeneration in FRDA, illustrating that NfL, GFAP, and UCHL1 are significantly raised in FRDA compared to aged-matched control. These observations may serve as the basis of further exploration of these brain-derived proteins as promising biomarkers in FRDA. In addition, we show for the first time in vivo an increase of GFAP reflecting astrocyte activation. This is confirmatory of in vitro studies suggesting a role of astrocytes in FRDA pathology. Finally, UCHL1 increase may reflect non-specific neuronal damage or alterations in the UPP. Future studies are needed to confirm our findings and determine whether, when applied to more heterogeneous cohorts, they serve as useful markers of disease severity.

Neuromuscular diseases with hypertrophic cardiomyopathy

Cesar S.; Global Cardiology Science and Practice 2018:27 doi:10.21542/gcsp.2018.27

Patient with FA and HCM have an early onset within the first or second decades with a poor correlation with the neurological level of disability. Histologically, left ventricle cellular hypertrophy, diffuse fibrosis and focal myocardial necrosis have been described. Echocardiographic hallmark is a concentric LV hypertrophy with absence of left ventricular outflow tract obstruction, but eccentric hypertrophy might be present.
There is no specific treatment for HCM in FA patients. Management of heart failure symptoms (salt restriction, diuretic therapy), ACE inhibitors or angiotensin II receptor blockers may be beneficial in long-term treatment. Treatment of atrial arrhythmias is mandatory, because the important atrial role to LV filling and cardiac output14. The drug idebenone acts as a transporter in the electron transport chain and has been advocated for use in FA following studies showing mild diastolic improvement and reduction LVH21,22. However, further trials have shown no benefit. Cardiac transplantation is not commonly performed, due to advanced impairment of both motor skills and muscle strength.

Longitudinal dentate nuclei iron concentration and atrophy in Friedreich ataxia: IMAGE-FRDA

Phillip Ward, Ian H Harding, Thomas G Close, Louise A Corben, Martin B Delatycki, Elsdon Storey, Nellie Georgiou-Karistianis, Gary F. Egan. bioRxiv 464537; doi: 10.1101/464537 (This article is a preprint and has not been peer-reviewed)

Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.

Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia

Lynch, D. R., Farmer, J. , Hauser, L. , Blair, I. A., Wang, Q. Q., Mesaros, C. , Snyder, N. , Boesch, S. , Chin, M. , Delatycki, M. B., Giunti, P. , Goldsberry, A. , Hoyle, C. , McBride, M. G., Nachbauer, W. , O'Grady, M. , Perlman, S. , Subramony, S. H., Wilmot, G. R., Zesiewicz, T. and Meyer, C. (2018), Ann Clin Transl Neurol. . doi:10.1002/acn3.660

Treatment of Friedreich ataxia patients with omaveloxolone at the optimal dose level of 160 mg/day appears to improve neurological function. Therefore, omaveloxolone treatment is being examined in greater detail at 150 mg/day for Friedreich ataxia.

Transcriptional profiling of isogenic Friedreich ataxia induced pluripotent stem cell-derived neurons

Jiun-I Lai, Daniel Nachun, Lina Petrosyan, Benjamin Throesch, Erica Campau, Fuying Gao, Kristin K Baldwin, Giovanni Coppola, Joel M Gottesfeld, Elisabetta Soragni; bioRxiv 457093; doi: 10.1101/457093

We find that multiple cellular pathways are commonly affected by the loss of frataxin in CNS and peripheral nervous system neurons and these changes are partially restored by HDACi treatment.

Emerging Regulatory Role of Nrf2 in Iron, Heme, and Hemoglobin Metabolism in Physiology and Disease.

Kasai Shuya, Mimura Junsei, Ozaki Taku, Itoh Ken. Frontiers in Veterinary Science 5,242 2018 DOI=10.3389/fvets.2018.00242

In this review article, we describe and discuss the roles of Nrf2 in various iron-mediated bioreactions and its possible coevolution with iron and oxygen. Nrf2 regulates a wide range of cytoprotective responses and protects cells against various diseases and toxicities. In this review, we will focus on the Nrf2-mediated cytoprotective response achieved by iron regulation and detoxification.

Patients in research: still many roadblocks

Roos Eric C. BMJ 2018; 363 :k4387 doi:10.1136/bmj.k4387

Patient involvement is receiving increasing support as it can improve speed and quality of projects. At the same time, there is still significant resistance against it among doctors, investigators, and project managers. This “mental roadblock” must be fully removed to get the projected benefits.

Full partnership with patients is essential to any modern research enterprise

Wicks Paul, Richards Tessa, Denegri Simon, Godlee Fiona. Patients’ roles and rights in research BMJ 2018; 362 :k3193  doi:10.1136/bmj.k3193

Patient and public involvement in research is becoming a mainstream activity thanks to recognition by everyone in the research process from funders and regulators to conference organisers and publishers that it helps them do a better job.
Including patients and the public as partners in research is accepted best practice in several Western countries, and some funders make it mandatory.

Patients’ roles and rights in research- Patients in research: one step in a long path

Wicks P, Richards T, Denegri S, Godlee F. BMJ 2018;362:k3193. 10.1136/bmj.k3193 30045909

We need to engage patients with mobility, or other, limitations due to their disease. These are the patients that clinical research is working to help, so their inclusion is vital.

Unraveling the Role of Heme in Neurodegeneration

Chiabrando Deborah, Fiorito Veronica, Petrillo Sara, Tolosano Emanuela. Frontiers in Neuroscience 12 (2018) 712 DOI=10.3389/fnins.2018.00712

Heme (iron-protoporphyrin IX) is an essential co-factor involved in several biological processes, including neuronal survival and differentiation. Conversely, an excess of free-heme promotes oxidative stress and lipid peroxidation thus leading to cell death. The toxic properties of heme in the brain have been extensively studied during intracerebral or subarachnoid haemorrhages. Recently, a growing number of neurodegenerative disorders have been associated to alterations of heme metabolism. Hence, the etiology of such diseases remains undefined. The aim of this review is to highlight the neuropathological role of heme and to discuss the major heme-regulated pathways that might be crucial for the survival of neuronal cells. The understanding of the molecular mechanisms linking heme to neurodegeneration will be important for therapeutic purposes.

The impact of histone post-translational modifications in neurodegenerative diseases

Samantha N. Cobos, Seth A. Bennett, Mariana P. Torrente, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.10.019.

Several histone PTMs have been associated with FRDA. One of the main causes of FRDA is the triplet repeat expansion GAA responsible for the transcriptional silencing of the FXN gene. Lymphoid cell lines from FRDA patients revealed that H3K4me2 and H3K4me marks decreased in the area surrounding the triplet repeat expansion when compared to unaffected cells. Moreover, both human tissues and a transgenic mice model showed an overall decrease in H3K9ac levels accompanied by increases in H3K9me2 and H3K9me3 levels. Collectively, these changes in histone marks would lead to lowered transcription, strongly suggesting that this is part of the mechanism that defines FRDA pathology.
In FRDA, treatment with nicotinamide (vitamin B3), an HDAC inhibitor, resulted in upregulation of the FXN gene by way of decreasing H3K9me3 and H3K27me3 at the FXN gene, and consequently increasing histone acetylation in both H3 and H4. This revels a possible treatment for FRDA, especially when considering the widespread availability, tolerability and affordability of vitamin B3.

Non-invasive Focal Mechanical Vibrations Delivered by Wearable Devices: An Open-Label Pilot Study in Childhood Ataxia

Schirinzi, T., Romano, A., Favetta, M., Sancesario, A., Burattini, R., Summa, S., Della Bella, G., Castelli, E., Bertini, E., Petrarca, M., … Vasco, G. (2018). Frontiers in neurology, 9, 849. doi:10.3389/fneur.2018.00849

Non-invasive focal mechanical vibrations (NIFMV) now represent a strategy of increasing interest to improve motor control in different neurological diseases. Nanotechnology allowed the creation of wearable devices transforming thermal variations into mechanical energy with focal vibrations. This kind of wearable stimulators (WS) has produced encouraging preliminary results when used in the treatment of movement disorders and ataxia in adults. In this open label pilot study we first evaluated the feasibility, safety and effectiveness of NIFMV by WS in a cohort of 10 patients with childhood ataxia, a phenomenological category including different conditions still lacking of effective symptomatic therapies. Through the assessment of both clinical rating scales and spatio-temporal gait parameters via standardized gait analysis, we observed that a 4 weeks long treatment with WS Equistasi® was safe and provided significantly different effects in stride features of patients with slow/non-progressive cerebellar ataxia and Friedreich's Ataxia.

A case series of hereditary cerebellar ataxias in a highly consanguineous population from Northeast Brazil

Deborah Moreira Rangel, Paulo Ribeiro Nóbrega, Maria Luiza Saraiva-Pereira, Laura Bannach Jardim, Pedro Braga-Neto, Parkinsonism & Related Disorders, 2018, ISSN 1353-8020, doi:10.1016/j.parkreldis.2018.10.027.

A total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%); The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3).
In contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.

Intraepidermal Nerve Fiber Density in Friedreich’s Ataxia

Elisabetta Indelicato, Wolfgang Nachbauer, Andreas Eigentler, Dagmar Rudzki, Julia Wanschitz, Sylvia Boesch; Journal of Neuropathology & Experimental Neurology, , nly100, doi:10.1093/jnen/nly100

In the present study, we aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in vivo. For this purpose, we evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg and applied clinical assessments of small fiber function (painDETECT, quantitative sensory testing) in 17 FRDAs.

Investigating the landscape of US orphan product approvals

Kathleen L. Miller and Michael Lanthier, Orphanet Journal of Rare Diseases 2018 13:183, doi:10.1186/s13023-018-0930-3

The Orphan Drug Act was enacted in 1983 to encourage the development of drugs for rare diseases. Previous research has attempted to examine the impact of the Act by assessing either the number of orphan designations that have been granted or the number of new orphan drugs approved for marketing. This study provides a more in-depth understanding of the effect of the Orphan Drug Act by investigating all types of drug approvals with an orphan designation, along with multiple characteristics of the drugs, over the entire 35 years of the Act. These orphan approvals include: new molecular entities (new drugs approved first for a rare disease), secondary indications (an expansion from the first approved indication), and new formulations.

The deoxyribose phosphate lyase of DNA polymerase β suppresses a processive DNA synthesis to prevent trinucleotide repeat instability

Yanhao Lai, Yossi Weizmann, Yuan Liu. Nucleic Acids Research, Volume 46, Issue 17, 28 September 2018, Pages 8940–8952, Doi:10.1093/nar/gky700

The results indicate that pol β dRP lyase activity restrained the pol β-dRP interaction to suppress a pol β processive DNA synthesis, thereby preventing TNR deletion. This further implicates a potential of pol β dRP lyase inhibition as a novel treatment of TNR-expansion diseases.

Ion Mobility-Mass Spectrometry Reveals Details of Formation and Structure for GAA·TCC DNA and RNA Triplexes

Jiawei Li, Alexander Begbie, Belinda J. Boehm, Alexander Button, Charles Whidborne, Yannii Pouferis, David M. Huang, Tara L. Pukala. J. Am. Soc. Mass Spectrom. (2018). https://doi.org/10.1007/s13361-018-2077-9

DNA and RNA triplexes are thought to play key roles in a range of cellular processes such as gene regulation and epigenetic remodeling and have been implicated in human disease such as Friedreich’s ataxia. In this work, ion mobility-mass spectrometry (IM-MS) is used with supporting UV-visible spectroscopy to investigate DNA triplex assembly, considering stability and specificity, for GAA·TTC oligonucleotide sequences of relevance to Friedreich’s ataxia. We demonstrate that, contrary to other examples, parallel triplex structures are favored for these sequences and that stability is enhanced by increasing oligonucleotide length and decreasing pH. We also provide evidence for the self-association of these triplexes, consistent with a proposed model of higher order DNA structures formed in Friedreich’s ataxia. By comparing triplex assembly using DNA- and RNA-based triplex-forming oligonucleotides, we demonstrate more favorable formation of RNA triplexes, suggesting a role for their formation in vivo.

New Perspectives in Iron Chelation Therapy for the Treatment of Neurodegenerative Diseases

Nuñez, M.T.; Chana-Cuevas, P. Pharmaceuticals 2018, 11, 109. doi:10.3390/ph11040109


Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.

Ferrochelatase activity of plant frataxin

Alejandro M. Armas, Manuel Balparda, Agustina Terenzi, Maria V. Busi, Maria A. Pagani, Diego F. Gomez-Casati, Biochimie, 2018 doi:10.1016/j.biochi.2018.10.009

These results suggest that frataxin could be the iron donor in the final step of heme synthesis in plant mitochondria, and constitutes an important advance in the elucidation of the mechanisms of heme synthesis in plants.

Calcium Deregulation: Novel Insights to Understand Friedreich’s Ataxia Pathophysiology

Abeti R, Brown AF, Maiolino M, Patel S and Giunti P (2018) . Front. Cell. Neurosci. 12:264. doi: 10.3389/fncel.2018.00264

Friedreich’s Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. Heart failure is one of the most common causes of death for FRDA patients. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. The focus of our study was to investigate the unexplored Ca2+ homeostasis in cerebellar granule neurons (CGNs) and in cardiomyocytes of FRDA cellular models to understand the pathogenesis of degeneration. Ca2+ homeostasis in neurons and cardiomyocytes is not only crucial for the cellular wellbeing but more importantly to generate action potential in both neurons and cardiomyocytes. By challenging Ca2+ homeostasis in CGNs, and in adult and neonatal cardiomyocytes of FRDA models, we have assessed the impact of frataxin decrease on both neuronal and cardiac physiopathology. Interestingly, we have found that Ca2+ homeostasis is altered both cell types. CGNs showed a Ca2+ mishandling under depolarizing conditions and this was also reflected in the endoplasmic reticulum (ER) content. In cardiomyocytes we found that the sarcoplasmic reticulum (SR) Ca2+ content was pathologically reduced, and that mitochondrial Ca2+ uptake was impaired. This phenomenon is due to the excess of oxidative stress under FRDA like conditions and the consequent aberrant modulation of key players at the SR/ER and mitochondrial level that usually restore the Ca2+ homeostasis. Our findings demonstrate that in both neurons and cardiomyocytes the decreased Ca2+ level within the stores has a comparable detrimental impact in their physiology. In cardiomyocytes, we found that ryanodine receptors (RyRs) may be leaking and expel more Ca2+ out from the SR. At the same time mitochondrial uptake was altered and we found that Vitamin E can restore this defect. Moreover, Vitamin E protects from cell death induced by hypoxia-reperfusion injury, revealing novel properties of Vitamin E as potential therapeutic tool for FRDA cardiomyopathy.

Developmental and Neurodegenerative Damage in Friedreich Ataxia

Rezende TJR, Martinez ARM, Faber I, Girotto K, Martins MP, de Lima FD, Lopes-Cendes I, Cendes F, França MC; Eur J Neurol. Accepted Author Manuscript. . doi:10.1111/ene.13843

Structural damage in FRDA begins in spinal cord, inferior cerebellar peduncle as well as red nucleus, and progresses to cerebral areas in adulthood. These results shed some light in the early FRDA stages and highlight potential neuroimaging markers for therapeutic trials.

Corneal Confocal Microscopy: Neurologic Disease Biomarker in Friedreich's Ataxia

Odelya E. Pagovich MD Mary L. Vo MD Zijun Zhao BA Ioannis N. Petropoulos PhD Michelle Yuan BA Buntitar Lertsuwanroj MD Jessica Ciralsky MD Edward Lai MD Szilard Kiss MD Donald J. D'Amico MD Jason G. Mezey PhD Rayaz A. Malik PhD Ronald G. Crystal MD; Ann Neurol. Accepted Author Manuscript. First published: 07 October 2018, doi:10.1002/ana.25355

CCM demonstrated a significant reduction in nerve fiber density and length in FRDA compared to healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parameters generated equations that predict the neurologic severity of FRDA.

Mitochondrial Targeting in Neurodegeneration: A Heme Perspective

Veronica Fiorito, Deborah Chiabrando and Emanuela Tolosano; Pharmaceuticals 2018, 11(3), 87; doi:10.3390/ph11030087

Mitochondrial dysfunction has achieved an increasing interest in the field of neurodegeneration as a pathological hallmark for different disorders. The impact of mitochondria is related to a variety of mechanisms and several of them can co-exist in the same disease. The central role of mitochondria in neurodegenerative disorders has stimulated studies intended to implement therapeutic protocols based on the targeting of the distinct mitochondrial processes. The review summarizes the most relevant mechanisms by which mitochondria contribute to neurodegeneration, encompassing therapeutic approaches. Moreover, a new perspective is proposed based on the heme impact on neurodegeneration. The heme metabolism plays a central role in mitochondrial functions, and several evidences indicate that alterations of the heme metabolism are associated with neurodegenerative disorders. By reporting the body of knowledge on this topic, the review intends to stimulate future studies on the role of heme metabolism in neurodegeneration, envisioning innovative strategies in the struggle against neurodegenerative diseases.

Automated functional upper limb evaluation of patients with Friedreich ataxia using serious games rehabilitation exercises

Bruno Bonnechère, Bart Jansen, Inès Haack, Lubos Omelina, Véronique Feipel, Serge Van Sint Jan and Massimo Pandolfo; Journal of NeuroEngineering and Rehabilitation 201815:87 doi.org/10.1186/s12984-018-0430-7

The use of new technologies in rehabilitation, including SG, is becoming increasingly important. In this study demonstrated that it is possible to combine rehabilitation exercises using SG and automated upper limb functional assessment in FRDA patients in wheelchairs. Future works are needed to determine if such kind of solution can be successfully integrated in the rehabilitation program and whether the kind of data presented in this paper can be used to predict disease progression.

Electrophysiological study of patients with spinocerebellar and Friedreich's ataxia

Blerim Myftiu, Mehmet Barış Baslo, Elif Kocasoy Orhan; Neurol Sci Neurophysiol 2018; 35: 138-144 DOI: 10.5152/NSN.2018.11239

Polyneuropathy is frequently detected in SCA and FRDA patients. The sensory nerves in lower extremities were predominantly involved; however motor dysfunction was also noted. MUNE can offer quantitative information on motor nerve fiber and motor neuron involvement. Nerve conduction studies and needle EMG demonstrate clinical or subclinical polyneuropathy in patients with SCA and FRDA ataxia. MUNE might present another parameter for peripheral involvement.

Effects of a wearable proprioceptive stabilizer on kinematics and spatio-temporal gait parameters in young with genetic ataxias

A. Romano, M. Favetta, T. Schirinzi, G. Vasco, S. Summa, S. Minosse, E. Castelli, M. Petrarca; Gait & Posture , Volume 66 , S33 Doi:10.1016/j.gaitpost.2018.07.152

Genetic ataxias are a degenerative disease of cerebellum, brain stem, and spinal cord, in which gait and limb ataxia are key clinical features. Focal mechanical vibration was found effective in improve limb and gait ataxia in adults with hereditary ataxias. Equistasi® is a medical wearable device composed by nanotechnology fibers that transform body temperature into mechanical able to generate a variation of muscle length of max 0.002 mm. This is a preliminary study to evaluate the effect of Equistasi® focal mechanical vibration on kinematic and spatio-temporal parameters in three young patients with genetic ataxias through 3D gait analysis.

The importance of central auditory evaluation in Friedreich's ataxia

Zeigelboim BS, Teive HAG, Rosa MRD, Malisky JS, Fonseca VR, Marques JM, Liberalesso PB. Arq Neuropsiquiatr. 2018 Mar;76(3):170-176. doi: 10.1590/0004-282x20180008.

Objective To assess central auditory function in Friedreich's ataxia. Methods A cross-sectional, retrospective study was carried out. Thirty patients underwent the anamnesis, otorhinolaryngology examination, pure tone audiometry, acoustic immittance measures and brainstem auditory evoked potential (BAEP) assessments. Results The observed alterations were: 43.3% in the pure tone audiometry, bilateral in 36.7%; 56.6% in the BAEP test, bilateral in 50%; and 46.6% in the acoustic immittance test. There was a significant difference (p < 0.05) in the comparison between the tests performed. Conclusion In the audiological screening, there was a prevalence of the descending audiometric configuration at the frequency of 4kHz, and absence of the acoustic reflex at the same frequency. In the BAEP test, there was a prevalence of an increase of the latencies in waves I, III and V, and in the intervals of interpeaks I-III, I-V and III-V. In 13.3% of the patients, wave V was absent, and all waves were absent in 3.3% of patients.

Functional and Structural Brain Damage in Friedreich's Ataxia

Vavla Marinela, Arrigoni Filippo, Nordio Andrea, De Luca Alberto, Pizzighello Silvia, Petacchi Elisa, Paparella Gabriella, D'Angelo Maria Grazia, Brighina Erika, Russo Emanuela, Fantin Marianna, Colombo Paola, Martinuzzi Andrea; Front. Neurol., 06 September 2018 doi.:10.3389/fneur.2018.00747

Our study demonstrates the extent of CNS brain damage in FRDA by using a composite protocol of clinical and multimodal neuroimaging tools as VBM, DTI and fMRI in a cross-sectional study. Our findings support the need for future longitudinal studies and highlights the possibility that MRI studies could provide valuable paraclinical biomarkers in FRDA.
In conclusion, our multimodal imaging study provided convergent results, with a strong involvement of the cerebellar cortex, cerebellar WM tracts, in particular SCPs and ICPs and a strong functional involvement of the anterior lobe of the cerebellum during the non-dominant hand motor task. These findings bring a new dimensional role of the cortical circuitry involved in FRDA.

Young couples from Paphos advised to get checked for rare disease before having kids

CyprusMail online, September 26th, 2018 Evie Andreou: Young couples, especially from Paphos, ought to get tested before deciding to have children to discover if they are at a high risk of having a child with the rare Ataxia disease, the Institute of Neurology and Genetics (CING) said on Tuesday.
n a written statement to mark International Ataxia Awareness Day – September 25 – CING said that in Cyprus high rates of patients have been identified in the Paphos district. Following a study in 2001-2002 it was found that about one in 12 people are carriers in the wider Paphos district. The frequency of carriers in European populations ranges between one in 50 to one in 100 people.

Chemical synthesis of lipophilic methylene blue analogues which increase mitochondrial biogenesis and frataxin levels.

Indrajit Bandyopadhyay, Sandipan Roy Chowdhury, Nishant P. Visavadiya, Sidney M. Hecht, Omar M. Khdour, Data in Brief, Volume 20, 2018,
Pages 1105-1114, doi:10.1016/j.dib.2018.08.156

As part of an ongoing program to develop potential therapeutic agents for the treatment of the neurodegenerative disease Friedreich׳s ataxia (FRDA), we have prepared a number of lipophilic methylene blue analogues. Some of these compounds significantly increase mitochondrial biogenesis and frataxin levels in cultured Friedreich’s ataxia cells . This data article describes the chemical synthesis and full physicochemical characterization of the new analogues.

Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

Alsina, D.; Purroy, R.; Ros, J.; Tamarit, J.; Pharmaceuticals 2018, 11, 89. doi:10.3390/ph11030089

Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. Many evidences indicate that frataxin deficiency causes the deregulation of cellular iron homeostasis. In this review, we will discuss several hypotheses proposed for frataxin function, their caveats, and how they could provide an explanation for the deregulation of iron homeostasis found in frataxin-deficient cells.

Single rod instrumentation in patients with scoliosis and co-morbidities: Indications and outcomes

Athanasios I Tsirikos, Peter R Loughenbury; World J Orthop. Sep 18, 2018; 9(9): 138-148 doi: 10.5312/wjo.v9.i9.138

Patients with complex deformities: This group included 62 complex patients with severe deformities and associated co-morbidities (Tables 1-3 and Figure 2). Underlying scoliosis diagnosis included syndromic (21 patients, Table 3), early onset idiopathic (17 patients; juvenile: 9, infantile: 8), congenital (13 patients), neuromuscular (5 patients; congenital myopathy: 1, cerebral palsy: 1, demyelinating neuropathy: 1, Friedreich’s ataxia: 1, congenital hypotonia: 1), and scoliosis associated with intraspinal anomalies (6 patients; Chiari I malformation with syringomyelia: 4, astrocytoma: 1, gaglioglioma: 1). Indications to use the single rod technique were high risk of neurological/cardiac complications, complex congenital vertebral anomalies, increased intra-operative bleeding, and low BMI.

Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide

Sabbah, H.N., Gupta, R.C., Singh-Gupta, V. et al. Cardiovasc Drugs Ther (2018) 32: 319. doi:10.1007/s10557-018-6805-y

Treatment with ELAM was also shown to normalize MITO morphology in kidneys of aging mice, in rats with acute kidney injury due to ischemia reperfusion, and improved MITO ultrastructure and morphology in lymphoblasts and fibroblasts derived from patients with Friedreich ataxia.

Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia

Karen A.G. Takazaki, Thiago Junqueira R. Rezende, Alberto R.M. Martinez, Carelis González, Anamarli Nucci, Iscia Lopes-Cendes, Marcondes C. França, Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia, Clinical Neurophysiology, 2018, doi:10.1016/j.clinph.2018.08.017.

We found abnormal sudomotor but normal heart rate variability in FRDA. Small cholinergic post-ganglionic fibers are affected in the disease.

Friedreich’s Ataxia: Clinical Presentation of a Compound Heterozygote Child with a Rare Nonsense Mutation and Comparison with Previously Published Cases

Vamshi K. Rao, Christine J. DiDonato and Paul D. Larsen; Case Reports in Neurological Medicine Volume 2018, Article ID 8587203, 5 pages doi:10.1155/2018/8587203

In conclusion, if the index of suspicion is high for Friedrich’s ataxia then frataxin sequencing should be performed if there is a repeat expansion detected only on one allele. Secondly, for the most part, compound heterozygous patients have an earlier age of onset that directly correlates with the trinucleotide expansion size. Finally, whether there is a unique phenotype to the nonsense mutations requires further study before counseling families regarding natural history of disease.

Magnetic susceptibility of the dentate in a longitudinal study of Friedreich ataxia

Phillip G D Ward, Ian H Harding, Parnesh Raniga, Tom G Close, Louise A Corben, Martin B Delatycki, Monique R Stagnitti, Elsdon Storey, Nellie Georgiou-Karistianis, and Gary F Egan; International Society for Magnetic Resonance in Medicine, (Abstract #3731) 16-21 June 2018 Paris (France)

We performed in-vivo measurements of the magnetic susceptibility in the dentate nucleus in individuals with Friedreich ataxia and healthy controls over a two-year longitudinal study using quantitative susceptibility mapping. The results show a significant susceptibility difference between individuals with Friedreich ataxia and control subjects, and a strong correlation with disease severity in the Friedreich ataxia cohort. These findings may lead to the development of a sensitive biomarker of disease severity and progression in Friedreich ataxia.

Regional cortical folding morphometry in Friedreich ataxia using Laplace Beltrami based gyrification index

Rosita Shishegar, Imis Dogan, Martin B. Delatycki, Gary F. Egan, Elsdon Storey, Louise A. Corben, and Nellie Georgiou-Karistianis; International Society for Magnetic Resonance in Medicine, (Abstract #3616) 16-21 June 2018 Paris (France)

Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder mainly affecting the spinal cord and dentate nuclei of the cerebellum. Although there is growing evidence of cerebral atrophy and cortical thinning in FRDA, no research has investigated the pattern of cortical folding (gyrification) in the disorder. We have proposed a new MRI analysis technique, Laplace Beltrami based gyrification index (LB-GI), and validated its use in individuals with FRDA. Preliminary results reveal significantly increased regional gyrification in the motor cortex in individuals with FRDA, compared to healthy controls. Overall, our results demonstrate that LB-GI is a sensitive technique which requires further investigation as a potential neuroimaging marker of disease progression in FRDA.

BRAIN FUNCTIONAL CHANGES CORRELATE WITH COGNITIVE DYSFUNCTION IN FRIEDREICH'S ATAXIA: AN RS-fMRI STUDY

Sirio Cocozza, Teresa Costabile, Enrico Tedeschi, Filomena Abate, Camilla Russo, Agnese Liguori, Walter Del Vecchio, Francesca Paciello, Mario Quarantelli, Alessandro Filla, Francesco Saccà, and Arturo Brunetti; International Society for Magnetic Resonance in Medicine, (Abstract #4670) 16-21 June 2018 Paris (France)

We performed a seed-based Resting-State fMRI analysis in Friedreich’s Ataxia (FRDA) patients to assess possible brain functional connectivity (FC) changes in these patients, which are know to be charactherized by an impairment of neuropsychological functions. We found an increased FC in FRDA patients compared to controls in different brain regions, including the medial frontal gryrus, the angular gyri and cingulate gyrus, with a decreased cerebellar FC. Our findings of diffuse alterations of FC in FRDA patients compared to controls may shed new light on the pattern of supratentorial and infratentorial involvement and on dynamics of brain plasticity in this condition.

Child Neurology: Friedreich ataxia with upper motor neuron findings

Elizabeth A. Harvey, Kimberly S. Jones; Neurology Aug 2018, 91 (9) 426-428; DOI: 10.1212/WNL.0000000000006086

A 16-year-old boy with hypertrophic cardiomyopathy, gait abnormalities, and balance problems was found to have Friedreich ataxia. Though Friedreich ataxia typically renders patients areflexic, this child had upper motor neuron findings of spasticity in both lower extremities, with crossed adductors, and 4+ deep tendon reflexes at the patella and Achilles bilaterally. This unusual presentation of an uncommon genetic disorder led to uncertainty of the patient's true diagnosis until genetic testing confirmed that he had 2 alleles with the Friedreich ataxia mutation.

DNA repair in trinucleotide repeat ataxias

Yau, W. Y., O'Connor, E. , Sullivan, R. , Akijian, L. and Wood, N. W. (2018), FEBS J. Accepted Author Manuscript. doi:10.1111/febs.14644

In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

Novel Epigenetic Techniques Provided by the CRISPR/Cas9 System.

Nina Xie, Yafang Zhou, Qiying Sun, and Beisha Tang, Stem Cells International, vol. 2018, Article ID 7834175, 12 pages, 2018. doi:10.1155/2018/7834175.

Other representative candidates may include the Rett syndrome, Huntington’s disease, and Friedreich ataxia, where dCas9-epieffector complex may be harnessed to restore or repress the responsible gene to cure the disease.

In conclusion, all of the studies described above indicated that CRISPR/Cas9-mediated epigenome editing holds a great promise for epigenetic studies and therapeutics. However, there are still some limitations to be scrutinized. First of all, in terms of basic science studies, although most studies claimed high specificity in their experiments, however, the high specificity usually is the result of repeated optimization. A precise model that could predict deleterious off-target effects during the experiment design stage is still lacking. In addition, although transactivation or repression effects on multiple genes were well documented in publications, mechanisms underlying the phenomenon were not clear. Epigenetic mark profiling on epigenome scale was not sufficient. Local CHIP-seq data usually only focused on the characterization of one or few histone marks. Theoretically, we hope that epigenome editing could achieve targeted gene regulation by changing epigenetic marks specifically and freely according to our wills. To achieve this goal, high specificity and clarified mechanisms are the prerequisite. Therefore, more thorough off-target event assessments and more studies focusing on mechanisms underlying epigenome editing are needed.

Moreover, in terms of clinical applications, several issues need to be addressed prior to successful clinical translation. Firstly, the endurance of gene activation or a repression effect mediated by CRISPR/Cas9 remains to be undetermined. It has been thought that epigenome-editing-induced gene activation or repression is short-term. On the contrary, there was also evidence showing that a gene silencing effect mediated by the hit-and-run epigenome editing strategy could also be long-term and inheritable. A short-term effect is more suitable for antagonizing acute pathogenic factor exposure and the transdifferentiation process. However, for treating chronic diseases, a long-term effect is expected. Additionally, a safer and efficient delivery method should be developed [92]. Adeno-associated virus (AAV) vectors have been the prevailing delivery method for some time. By tagging a synthetic surface peptide, splitting the Cas9 protein or using its smaller orthologues, and choosing a suitable administration route, researchers significantly improved the packaging capacity and delivery efficiency of AAV vectors. However, for clinical applications, more optimization is required. The immunogenicity of AAV vectors, dCas9 proteins, and guide RNAs should be determined precisely. The off-target effects of AAV vectors or dCas9-epieffector complex should be minimized as much as possible to ensure clinical safety.

Company hopes to speed up payments for clinical trial patients

(Action News) KING OF PRUSSIA, Pa. Wednesday, August 22, 2018
Clinical trials help drive medical advances. However, some patients hedge at taking part because reimbursement for their expenses take time.

Two years ago, Kyle took part in a test of ClinCard, a reloadable debit card. Once a patient's ClinCard is established, money is loaded after each research visit... no check, no cash. It's instant money for the patient, and instant documentation for the trial site.

PTC Therapeutics Successfully Completes Acquisition of Agilis Biotherapeutics

SOUTH PLAINFIELD, N.J., Aug. 23, 2018 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT), today announced that it has successfully completed the acquisition of Agilis Biotherapeutics, Inc., a private biotechnology company focused on the advancement of innovative gene therapy programs for rare genetic disorders that affect the central nervous system (CNS).
The acquisition also includes gene therapy programs in development, GT-FA, GT-AS, and GT-RLN, for Friedreich Ataxia, Angelman Syndrome and Cognitive Disorders associated with several neurodevelopmental and neurodegenerative disorders, respectively.

Longitudinal Diffusion Tensor Imaging in the brain in Friedreich’s Ataxia: follow-up at 12 and 24 months

Pierre-Gilles Henry, James Joers, Dinesh Deelchand, Diane Hutter, and Christophe Lenglet; International Society for Magnetic Resonance in Medicine, (Abstract #3730) 16-21 June 2018

We report 12-month and 24-month longitudinal diffusion tensor imaging (DTI) data in the brain of subjects with Friedreich’s ataxia (FRDA). Significant longitudinal changes were observed in several brain areas (including the corpus callosum, internal capsule and superior corona radiata) in a group of 13 patients over 24 months. Our data suggest that diffusion MRI of the brain could be useful to better understand the impact of FRDA on brain microstructure and connectivity, and to assess the effect of potential treatments on neurodegeneration in upcoming clinical trials in FRDA.

Noninvasive brain stimulation may help treat symptoms of rare movement disorders

August 22, 2018, American Academy of Neurology.
Electrical stimulation of the brain and spinal cord may help treat the symptoms of rare movement disorders called neurodegenerative ataxias, according to a study published in the August 22, 2018, online issue of Neurology, the medical journal of the American Academy of Neurology. There are several types of these disorders, which can be hereditary or occur randomly, including spinocerebellar ataxia, multiple system atrophy and Friedreich's ataxia.

Public summary of opinion on orphan designation: Omaveloxolone for treatment of Friedreich's ataxia

EMA/395368/2018, 16 August 2018

On 27 June 2018, orphan designation (EU/3/18/2037) was granted by the European Commission to Dr Stefan Blesse, Germany, for omaveloxolone (also known as RTA 408) for the treatment of Friedreich’s ataxia.
In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 24 May 2018 recommending the granting of this designation.

Jupiter Orphan Therapeutics Announces Favorable Data Which Expands JOTROL's Applications to the Estimated $5 Billion Mitochondrial Rare Disease Market

JUPITER, Fla., Aug. 22, 2018 /PRNewswire/ -- Jupiter Orphan Therapeutics, Inc. ("JOT"), Jupiter, FL, today announced that it has received new data regarding an increase in mitochondrial biogenesis in liver and brain from a recently performed study in a frequently studied Alzheimer's disease animal model, the triple transgenic (APPsw / PS1M146V / TauP301L) mouse.

Murdoch Children's Research Institute, a JOT partner, has conducted an open label study showing that high dose of resveratrol (not JOTROL), with associated GI-side effects, had significant positive impact in 4 vital endpoints. Target, for this indication, is to reproduce this study with JOTROL and reproduce the same positive results without side effects.

Test-retest reliability of an instrumented electronic walkway system (GAITRite) for the measurement of spatio-temporal gait parameters in young patients with Friedreich’s ataxia

Bastien Roche, Anne-Laure Simon, Sophie Guilmin-Crépon, Priscilla Boizeau, Béatrice Andriss, Corinne Alberti, Ana Presedo, Brice Ilharreborde, Isabelle Husson, Gait & Posture, 2018, doi:10.1016/j.gaitpost.2018.08.017.

The GAITRite system allows feasible and reliable measurements of gait parameters in young patients with FRDA. Lower reliability found for the weakest parameters was attributed to the software automatic errors and the ankle laxity noted in every patient.

Investigating Molecular Mechanisms Underlying Mild Phenotype in Friedreich Ataxia Patients with G130V Missense Mutation

Clark, Elisia. University of Pennsylvania, ProQuest Dissertations Publishing, 2018. 10748306. A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Ful fillment of the Requirements for the Degree of Doctor of Philosophy.

Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase

Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, et al. (2018) Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS ONE 13(8): e0201369. https://doi.org/10.1371/journal.pone.0201369

Genetic basis of hypertrophic cardiomyopathy in children

tefan Rupp, Moataz Felimban, Anne Schänzer, Dietmar Schranz, Christoph Marschall, Martin Zenker, Thushiha Logeswaran, Christoph Neuhäuser, Josef Thul, Christian Jux, Andreas Hahn; Clin Res Cardiol (2018). doi:10.1007/s00392-018-1354-8

42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich’s ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%).
A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.

Nonataxia symptoms in Friedreich Ataxia. Report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS)

Kathrin Reetz, Imis Dogan, Christian Hohenfeld, Claire Didszun, Paola Giunti, Caterina Mariotti, Alexandra Durr, Sylvia Boesch, Thomas Klopstock, Francisco Javier Rodríguez de Rivera Garrido, Ludger Schöls, Ilaria Giordano, Katrin Bürk, Massimo Pandolfo, Jörg B. Schulz, the EFACTS Study Group, Neurology Aug 2018, DOI: 10.1212/WNL.0000000000006121

The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems.

Gene therapy for neurological disorders: progress and prospects

Benjamin E. Deverman, Bernard M. Ravina, Krystof S. Bankiewicz, Steven M. Paul & Dinah W. Y. Sah; Nature Reviews Drug Discovery, Published: 10 August 2018 doi:10.1038/nrd.2018.110

Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

Longitudinal analysis of contrast acuity in Friedreich ataxia

Ali G. Hamedani, Lauren A. Hauser, Susan Perlman, Katherine Mathews, George R. Wilmot, Theresa Zesiewicz, S.H. Subramony, Tetsuo Ashizawa, Martin B. Delatycki, Alicia Brocht, David R. Lynch; Neurol Genet. 2018 Jul 23;4(4):e250. doi: 10.1212/NXG.0000000000000250. eCollection 2018 Aug.

Low-contrast visual acuity decreases linearly over time in Friedreich ataxia, and the rate of decrease is greater at higher GAA repeat lengths. Contrast sensitivity has the potential to serve as a biomarker and surrogate outcome in future studies of Friedreich ataxia.

Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR. Front Neurosci. 2018;12 . PMCID: PMC6048292.

Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis in vivo is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging. One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function. This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress. The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear. Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis

Novoheart, Pfizer develop 3-D model of Friedreich ataxia

VANCOUVER, British Columbia – June 25, 2018 (GLOBE NEWSWIRE) – Novoheart (“Novoheart” or the “Company”) (TSXV: NVH; FWB: 3NH) is pleased to announce a presentation was delivered on June 22nd, 2018, entitled “Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells,” at the Annual Meeting of the International Society for Stem Cell Research in Melbourne, Australia. The presentation includes data from research conducted with Pfizer Inc. on a 3D engineered human cardiac tissue disease model of Friedreich’s ataxia (FRDA), a neurodegenerative disease in which patients most often die of heart complications. The new disease model helps capture both electrical and mechanical defects of the heart observed in patients with FRDA.
“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine.” said Novoheart CSO, Dr. Kevin Costa.

The Effects of Game Based Exercise Training on Balance and Postural Control in Patients With Ataxia

ClinicalTrials.gov Identifier: NCT03607058

Patients who meet the inclusion criteria will be divided into two groups randomly: 'Kinect and exercise training' and 'exercise training'. The assessments will be made by a blind investigator four times, before and after the implementation of both protocols. The evaluations will take approximately 1 hour. The demographic information of the cases will be recorded. Designed as cross over study, two treatment protocols will be used in this study. The first protocol will be Xbox Kinect application plus exercise program, the second protocol will be only exercise program. At the beginning of the study, 2 groups will be allocated (Group A and Group B) randomly. For group A, the Xbox Kinect application plus exercise program will be applied for the first 8 weeks. For group B, only exercise program will be applied therapy first 8 weeks. All assessments will be repeated before and after each therapy period. Exercise program will consist of selected balance, coordination and walking exercises according to the individual needs of patients. . After 1 week washout period, patients will be included in the other group. All patients will take the treatment 1-hour, 3 days in a week for 8 weeks.

Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 13 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Ataksik Hastalarda Oyun Temelli Egzersiz Eğitiminin Denge ve Postural Kontrol Üzerine Etkisi
Actual Study Start Date : October 18, 2017
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : September 2018
Locations: Turkey, Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation

Public offering nets $203mm for Reata

Strategic Transactions. Jul 2018
Executive Summary
Reata Pharmaceuticals Inc. (developing drugs targeting molecular pathways that regulate inflammation and cellular metabolism) netted $203mm through the public sale of 3mm Class A common shares at $72. Some of the funds will support ongoing development of lead candidates bardoxolone methyl (Phase II/III for chronic kidney disease caused by Alport syndrome) and omaveloxolone (Phase II for Friedreich's ataxia), and to prepare for NDA filings and future commercialization.

Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia

Theresa Zesiewicz, Jason L Salemi, Susan Perlman, Kelly L Sullivan, Jessica D Shaw, Yangxin Huang, Charles Isaacs, Clifton Gooch, David R Lynch & Matthew B Klein; Neurodegenerative Disease Management [27 Jul 2018] doi:10.2217/nmt-2018-0013

Aim: To evaluate the safety and clinical effects of EPI-743 in Friedreich's ataxia patients. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism. Methods: We conducted a multicenter trial that evaluated EPI-743 during a 6-month placebo-controlled phase, followed by an 18-month open-label phase. End points included low-contrast visual acuity and the Friedreich's Ataxia Rating Scale. Results/conclusion: EPI-743 was demonstrated to be safe and well tolerated. There were no significant improvements in key end points during the placebo phase. However, at 24 months, EPI-743 treatment was associated with a statistically significant improvement in neurological function and disease progression relative to a natural history cohort (p > 0.001).

Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich’s Ataxia cells

Omar Khdour, Indrajit Bandyopadhyay, Nishant Visavadiya, Sandipan Roy Chowdhury, Sidney M Hecht; MedChemComm ( IF 2.342 ) Pub Date : 2018-07-26 , DOI: 10.1039/C8MD00274F

Friedreich’s ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously (1 and 2) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, 4b and 6b, exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.

Monash plant science discovery may unlock treatment strategies for genetic diseases in humans

SOURCE Monash University

SYDNEY, July 26, 2018 /PRNewswire/ -- Monash plant scientists have discovered a new molecular mechanism of gene regulation, which could have major implications for the development of treatment strategies for Friedreich's ataxia -- a debilitating genetic disorder that causes damage to the nervous system.

"This research has major implications for our understanding of how the genetic mutation that underlies Friedreich ataxia, leads to damage of the nervous system and thus symptoms of this condition," said Professor Martin Delatycki, a clinician and researcher from Murdoch Children's Research Institute who has studied Friedreich ataxia for more than 20 years.

RNA-Dependent Epigenetic Silencing Directs Transcriptional Downregulation Caused by In- tronic Repeat Expansions

Hannes Eimer, Sridevi Sureshkumar, Avilash Singh Yadav, Calvin Kraupner-Taylor, Champa Bandaranayake, Andrei Seleznev, Tamblyn Thomason, Stephen J. Fletcher, Stephanie Frances Gordon, Bernard J. Carroll, Sureshkumar Balasubramanian; Cell Cell 174, 1–11 August 23, 2018, doi:10.1016/j.cell.2018.06.044

we have demonstrated that triplet expansions in transcribed regions of the genome have the potential to generate siRNAs, which in turn can target the locus harboring the repeat expansion for epigenetic gene silencing. Epigenetic changes have been implicated in several triplet expansion disorders. It has also been suggested that the repeats that undergo expansion have a distinct association with epigenetic features. Our findings reinforce the importance of epigenetic changes in establishing the disease state caused by triplet repeat expansions. It would be interesting to assess whether siRNA-mediated epigenetic silencing is of significance in triplet expansion diseases such as FRDA in the human system. Future studies should explore additional components of this pathway involving chromatin modifications that result from trinucleotide repeat expansions.

Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia

Amandine Palandri, Elodie Martin, Maria Russi, Michael Rera, Hervé Tricoire, Véronique Monnier; Disease Models & Mechanisms 2018 11: dmm033811 doi: 10.1242/dmm.033811 Published 20 July 2018

This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.

PTC Therapeutics to Acquire Agilis Biotherapeutics

Medical Buyer Bureau. July 23, 2018. PTC Therapeutics to Acquire Agilis Biotherapeutics.

We are impressed with the clinical results shown by the AADC program and are excited with the potential to quickly bring this therapy to patients. We look forward to advancing the Friedreich ataxia and Angelman syndrome programs into the clinic in the next two years.”

Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity

Nicholas G. Fox, Alain Martelli, Joseph F. Nabhan, Jay Janz, Oktawia Borkowska, Christine Bulawa, Wyatt W. Yue, Biochimie, 2018, doi:10.1016/j.biochi.2018.07.012.

Human de novo iron-sulfur (Fe-S) assembly complex consists of cysteine desulfurase NFS1, accessory protein ISD11, acyl carrier protein ACP, scaffold protein ISCU, and allosteric activator frataxin (FXN). FXN binds the NFS1-ISD11-ACP-ISCU complex (SDAU), to activate the desulfurase activity and Fe-S cluster biosynthesis. In the absence of FXN, the NFS1-ISD11-ACP (SDA) complex was reportedly inhibited by binding of recombinant ISCU. Recent studies also reported a substitution at position Met141 on the yeast ISCU orthologue Isu, to Ile, Leu, Val, or Cys, could bypass the requirement of FXN for Fe-S cluster biosynthesis and cell viability. Here, we show that recombinant human ISCU binds zinc(II) ion, as previously demonstrated with the E. coli orthologue IscU. Surprisingly, the relative proportion between zinc-bound and zinc-depleted forms varies among purification batches. Importantly the presence of zinc in ISCU impacts SDAU desulfurase activity. Indeed, removal of zinc(II) ion from ISCU causes a moderate but significant increase in activity compared to SDA alone, and FXN can activate both zinc-depleted and zinc-bound forms of ISCU complexed to SDA. Taking into consideration the inhibition of desulfurase activity by zinc-bound ISCU, we characterized wild type ISCU and the M140I, M140L, and M140V variants under both zinc-bound and zinc-depleted conditions, and did not observe significant differences in the biochemical and biophysical properties between wild-type and variants. Importantly, in the absence of FXN, ISCU variants behaved like wild-type and did not stimulate the desulfurase activity of the SDA complex. This study therefore identifies an important regulatory role for zinc-bound ISCU in modulation of the human Fe-S assembly system in vitro and reports no ‘FXN bypass’ effect on mutations at position Met140 in human ISCU. Furthermore, this study also calls for caution in interpreting studies involving recombinant ISCU by taking into consideration the influence of the bound zinc(II) ion on SDAU complex activity

Genome damage from CRISPR/Cas9 gene editing higher than thought

ScienceDaily, 19 July 2018. Scientists at the Wellcome Sanger Institute have discovered that CRISPR/Cas9 gene editing can cause greater genetic damage in cells than was previously thought. These results create safety implications for gene therapies using CRISPR/Cas9 in the future as the unexpected damage could lead to dangerous changes in some cells.

Journal Reference:

Michael Kosicki, Kärt Tomberg, Allan Bradley. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nature Biotechnology, 2018; DOI: 10.1038/Nbt.4192

Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome

Salman OF, El-Rayess HM, Abi Khalil C, Nemer G and Refaat MM (2018). Front. Cardiovasc. Med. 5:77. doi: 10.3389/fcvm.2018.00077

Although triplet repeat expansion mutations are uncommon among dilated cardiomyopathys, some diseases like Friedreich's ataxia and some muscular dystrophies are associated with DCMs.

Sodium magnetic resonance imaging in Friedreich ataxia – A preliminary study

J.S. Krahe, S. Romanzetti, I. Dogan, C. Didszun, J.B. Schulz, K. Reetz, Clinical Neurophysiology, Volume 129, Issue 8, 2018, Pages e71-e72, doi:10.1016/j.clinph.2018.04.656.

The increase of TSC in cerebellum and brainstem in FRDA patients suggests the diagnostic potential of in vivo sodium MRI to differentiate between patients and controls. Moreover, this was related to more severe ataxia, as assessed by the SARA. These preliminary results support our hypothesis that sodium MRI may be a new imaging marker that could shed new insights into the metabolic pathophysiological mechanisms of FRDA.

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich’s Ataxia Models

Abeti R, Baccaro A, Esteras N and Giunti P (2018); Front. Cell. Neurosci. 12:188. doi: 10.3389/fncel.2018.00188

Omaveloxolone was protective to mitochondrial depolarization, promoting mitochondrial respiration and preventing cell death. Our results show that omav promotes Complex I activity and protect cells from oxidative stress. Omav could, therefore, be used as a novel therapeutic drug to ameliorate the pathophysiology of FRDA.

Activating frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion

Xiulong Shen, Audrius Kilikevicius, Daniel O'Reilly, Thazha P. Prakash, Masad J. Damha, Frank Rigo, David R. Corey, Bioorganic & Medicinal Chemistry Letters 2018, doi:10.1016/j.bmcl.2018.07.033.

Agents that increase expression of FXN protein are a potential approach to therapy. We previously described anti-trinucleotide GAA duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) that activate FXN protein expression in multiple patient derived cell lines. Here we test two distinct series of compounds for their ability to increase FXN expression. ASOs with butane linkers showed low potency, which is consistent with the low Tm values and suggesting that flexible conformation impairs activity. By contrast, single-stranded siRNAs (ss-siRNAs) that combine the strengths of dsRNA and ASO approaches had nanomolar potencies. ss-siRNAs provide an additional option for developing nucleic acid therapeutics to treat FRDA.

Inherited Cardiomyopathies and the Role of Mutations in Non-coding Regions of the Genome

Salman OF, El-Rayess HM, Abi Khalil C, Nemer G and Refaat MM (2018) Front. Cardiovasc. Med. 5:77. doi: 10.3389/fcvm.2018.00077

Reata Receives Orphan Drug Designation from the European Commission for Omaveloxolone for the Treatment of Friedreich’s Ataxia

IRVING, Texas, July 10, 2018 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA), a clinical-stage biopharmaceutical company, today announced that the European Commission has granted orphan drug designation for omaveloxolone for the treatment of Friedreich’s ataxia (FA), based on the positive opinion from the Committee for Orphan Medicinal Products of the European Medicines Agency (EMA).
Last year, Reata reported results from part 1 of MOXIe, a two-part, international, multi-center, randomized, double-blind, placebo-controlled Phase 2 trial studying the safety and efficacy of omaveloxolone in patients with FA. Treatment of FA patients with omaveloxolone produced dose- and time-dependent improvements in their modified Friedreich’s Ataxia Rating Scale (mFARS) scores, which are a measure of the neurologic function of FA patients. Reata is currently enrolling approximately 100 FA patients in the registrational part 2 portion of MOXIe and expects to have results in the second half of 2019.

The Cerebellum and Cognition

Jeremy D. Schmahmann, Neuroscience Letters, 2018, doi:10.1016/j.neulet.2018.07.005.

Structure function correlation studies following focal cerebellar lesions in adults and children permit a finer appreciation of the functional topography and nature of the cerebellar motor syndrome, cerebellar vestibular syndrome, and the third cornerstone of clinical ataxiology - the cerebellar cognitive affective syndrome. The ability to detect the cerebellar cognitive affective syndrome in real time in clinical neurology with a brief and validated scale should make it possible to develop a deeper understanding of the clinical consequences of cerebellar lesions in a wide range of neurological and neuropsychiatric disorders with a link to the cerebellum.

Impact of Drosophila Models in the Study and Treatment of Friedreich’s Ataxia

Monnier, V.; Llorens, J.V.; Navarro, J.A., Int. J. Mol. Sci. 2018, 19, 1989.

Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.

Architectural Features of Human Mitochondrial Cysteine Desulfurase Complexes from Crosslinking Mass Spectrometry and Small-Angle X-Ray Scattering

Kai Cai, Ronnie O. Frederick, Hesam Dashti, John L. Markley; Structure, 2018, doi:10.1016/j.str.2018.05.017.

We present a structural model for the cysteine desulfurase-ISCU-frataxin complex derived from chemical crosslinking restraints in conjunction with the recent crystal structure of the cysteine desulfurase-ISCU-zinc complex and distance constraints from nuclear magnetic resonance.

Targeting ERK signaling pathway by polyphenols as novel therapeutic strategy for neurodegeneration

Mohammad Hosein Farzaei, Devesh Tewari, Saeideh Momtaz, Sandro Argüelles, Seyed Mohammad Nabavi, Food and Chemical Toxicology, 2018, doi:10.1016/j.fct.2018.07.010.

Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism.

The Etiologies of Chronic Progressive Cerebellar Ataxia in a Korean Population

Kim JS, Kwon S, Ki CS, Youn J, Cho JW.; J Clin Neurol. 2018 Jul;14(3):374-380. Doi:10.3988/jcn.2018.14.3.374

Although the AR ataxias such as ataxia telangiectasia or FRDA are prevalent in most countries, they are extremely rare in the Korean population.26 In addition, genetic screening did not detect FRDA in the patients with undetermined ataxia. Therefore, routine screening of the FTX gene in the Korean population might not be needed unless patients show a clinical phenotype of FRDA.
FRDA is extremely rare, and to the best of our knowledge has never detected in the Korean population. In addition, phenotypes of patients in whom FRDA screening test was performed, did not correspond with FRDA.

Frataxin Restoration in the Nervous System: Possibilities for Gene Therapy

David R. Lynch, Elizabeth Kichula, and Hong Lin. Molecular Therapy, Available online 30 June 2018, ISSN 1525-0016, doi:10.1016/j.ymthe.2018.06.006

Many obstacles beyond those identified in the present study will appear in the translation of gene therapy from animal concept to human therapy. Still, the present work provides proof that gene therapy may be useful long term in FRDA, and hope for all those with this disorder.