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.