A case-control spectral analysis of sleep in Friedreich's Ataxia

R. Forbes, S.S. Smith, A. Ritchie, J.D. O'Sullivan, S. Mantovani, Sleep Medicine, Volume 40, Supplement 1, December 2017, Page e209, ISSN 1389-9457, doi:10.1016/j.sleep.2017.11.611.

This study shows that power spectral alterations are present in FA patients when compared to healthy controls. This may have impli- cations for understanding the nature of sleep difficulties in FA, while their role in the progression of disease remains uncertain.

Emerging therapeutics for the treatment of Friedreich’s ataxia

Elisabetta Indelicato & Sylvia Bösch; Expert Opinion on Orphan Drugs Vol. 6 , Iss. 1,2018 doi:10.1080/21678707.2018.1409109

Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.

Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases

Gerwyn Morris, Michael Berk, André F. Carvalho, Michael Maes, Adam J. Walker, Basant K. Puri, Behavioural Brain Research, Available online 28 December 2017, ISSN 0166-4328, doi:10.1016/j.bbr.2017.12.036.

Ferroptosis is a unique form of programmed death, characterised by cytosolic accumulation of iron, lipid hydroperoxides and their metabolites, and effected by the fatal peroxidation of polyunsaturated fatty acids in the plasma membrane. It is a major driver of cell death in neurodegenerative neurological diseases. Moreover, cascades underpinning ferroptosis could be active drivers of neuropathology in major psychiatric disorders. Oxidative and nitrosative stress can adversely affect mechanisms and proteins governing cellular iron homeostasis, such as the iron regulatory protein/iron response element system, and can ultimately be a source of abnormally high levels of iron and a source of lethal levels of lipid membrane peroxidation. Furthermore, neuroinflammation leads to the upregulation of divalent metal transporter-1 on the surface of astrocytes, microglia and neurones, making them highly sensitive to iron overload in the presence of high levels of non-transferrin-bound iron, thereby affording such levels a dominant role in respect of the induction of iron-mediated neuropathology. Mechanisms governing systemic and cellular iron homeostasis, and the related roles of ferritin and mitochondria are detailed, as are mechanisms explaining the negative regulation of ferroptosis by glutathione, glutathione peroxidase 4, the cysteine/glutamate antiporter system, heat shock protein 27 and nuclear factor erythroid 2-related factor 2. The potential role of DJ-1 inactivation in the precipitation of ferroptosis and the assessment of lipid peroxidation are described. Finally, a rational approach to therapy is considered, with a discussion on the roles of coenzyme Q10, iron chelation therapy, in the form of deferiprone, deferoxamine (desferrioxamine) and deferasirox, and N-acetylcysteine.

Association between iron related gene polymorphisms and Friedreich’s ataxia (FRDA) disease and peripheral neuropathy in Indian cohort

I. Singh, S. Shakya, R.K. Singh, A. Istaq, V. Goyal, S. Garima, A.K. Srivastava; Journal of the Neurological Sciences Volume 381, Supplement, 15 October 2017, Pages 895 Doi: 10.1016/j.jns.2017.08.2519

Till date, this is the largest study investigating HFE variations in FRDA. The observed over representation of p.H63D variation in FRDA and its correlation with the occurrence of peripheral neuropathy is intriguing in the context of dysregulated iron metabolism in FRDA due to loss of function mutations in FXN.

Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurodegenerative disease trajectory.

Scott W. Burnside, Giles E. Hardingham; Biochemical Society Transactions Nov 17, 2017, 45 (6) 1295-1303; DOI: 10.1042/BST20170013

Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory.

NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR

Jun Yoshino, Joseph A. Baur, Shin-ichiro Imai,  Cell Metabolism, Available online 14 December 2017, ISSN 1550-4131, doi:10.1016/j.cmet.2017.11.002.

Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health.

Friedreich and dominant ataxias: quantitative differences in cerebellar dysfunction measurements

Tanguy Melac A, Mariotti C, Filipovic Pierucci A on behalf of the EFACTS group, et al; J Neurol Neurosurg Psychiatry Published Online First: 26 December 2017. doi: 10.1136/jnnp-2017-316964

Cerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated.

The International Rare Diseases Research Consortium: Policies and Guidelines to maximize impact

Hanns Lochmüller, Josep Torrent i Farnell, Yann Le Cam, Anneliene H Jonker, Lilian PL Lau, Gareth Baynam, Petra Kaufmann, Hugh JS Dawkins, Paul Lasko, Christopher P Austin, Kym M Boycott & on behalf of the IRDiRC Consortium Assembly; European Journal of Human Genetics 25, 1293–1302 (2017) doi:10.1038/s41431-017-0008-z

The IRDiRC Policies and Guidelines are the first, detailed agreement of major public and private funding organizations worldwide to govern rare disease research, and may serve as a template for other areas of international research collaboration. While it is too early to assess their full impact on research productivity and patient benefit, the IRDiRC Policies and Guidelines have already contributed significantly to improving transparency and collaboration in rare disease research.

Exploring patient and family involvement in the lifecycle of an orphan drug: a scoping review

Andrea Young, Devidas Menon, Jackie Street, Walla Al-Hertani and Tania Stafinski; Orphanet Journal of Rare Diseases 201712:188 doi:10.1186/s13023-017-0738-6

Patients and their families have become more active in healthcare systems and research. The value of patient involvement is particularly relevant in the area of rare diseases, where patients face delayed diagnoses and limited access to effective therapies due to the high level of uncertainty in market approval and reimbursement decisions. It has been suggested that patient involvement may help to reduce some of these uncertainties. This review explored existing and proposed roles for patients, families, and patient organizations at each stage of the lifecycle of therapies for rare diseases (i.e., orphan drug lifecycle).

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia

Hong Lin, Jordi Magrane, Elisia M. Clark, Sarah M. Halawani, Nathan Warren, Amy Rattelle, David R. Lynch; Disease Models & Mechanisms 2017 10: 1529-1538; doi: 10.1242/dmm.030049

Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model.

Liquid Chromatography-High Resolution Mass Spectrometry Analysis of Platelet Frataxin as a Protein Biomarker for the Rare Disease Friedreich’s Ataxia

Lili Guo, Qingqing Wang, Liwei Weng, Lauren A. Hauser, Cassandra J. Strawser, Agostinho G. Rocha, Andrew Dancis, Clementina A Mesaros, David R. Lynch, and Ian Alexander Blair; Anal. Chem., Just Accepted Manuscript DOI: 10.1021/acs.analchem.7b04590 Publication Date (Web): December 22, 2017

Frataxin is undetectable in serum or plasma, and whole blood cannot be used because it is present in long-lived erythrocytes. Therefore, an assay was developed for analyzing frataxin in platelets, which have a half-life of 10-days. The assay is based on stable isotope dilution immunopurification two-dimensional nano-ultrahigh performance liquid chromatography/parallel reaction monitoring/mass spectrometry. The lower limit of quantification was 0.078 pg frataxin/μg protein and the assay had 100% sensitivity and specificity for discriminating between controls and FA cases. The mean levels of control and FA platelet frataxin were 9.4 2.6 pg/g protein and 2.4 0.6 pg/g protein, respectively. The assay should make it possible to rigorously monitor the effects of therapeutic interventions on frataxin expression in this devastating disease.

Somatic instability of the expanded GAA repeats in Friedreich’s ataxia

Ashlee Long, Jill S. Napierala, Urszula Polak, Lauren Hauser, Arnulf H. Koeppen, David R. Lynch, Marek Napierala; PLoS ONE 12(12): e0189990. Doi:10.1371/journal.pone.0189990

Friedreich’s ataxia (FRDA) is a genetic neurodegenerative disorder caused by transcriptional silencing of the frataxin gene (FXN) due to expansions of GAA repeats in intron 1. FRDA manifests with multiple symptoms, which may include ataxia, cardiomyopathy and diabetes mellitus. Expanded GAA tracts are genetically unstable, exhibiting both expansions and contractions. GAA length correlates with severity of FRDA symptoms and inversely with age of onset. Thus, tissue-specific somatic instability of long GAA repeats may be implicated in the development of symptoms and disease progression. Herein, we determined the extent of somatic instability of the GAA repeats in heart, cerebral cortex, spinal cord, cerebellar cortex, and pancreatic tissues from 15 FRDA patients. Results demonstrate differences in the lengths of the expanded GAAs among different tissues, with significantly longer GAA tracts detected in heart and pancreas than in other tissues. The expansion bias detected in heart and pancreas may contribute to disease onset and progression, making the mechanism of somatic instability an important target for therapy. Additionally, we detected significant differences in GAA tract lengths between lymphocytes and fibroblast pairs derived from 16 FRDA patients, with longer GAA tracts present in the lymphocytes. This result urges caution in direct comparisons of data obtained in these frequently used FRDA models. Furthermore, we conducted a longitudinal analysis of the GAA repeat length in lymphocytes collected over a span of 7–9 years and demonstrated progressive expansions of the GAAs with maximum gain of approximately 9 repeats per year. Continuous GAA expansions throughout the patient’s lifespan, as observed in FRDA lymphocytes, should be considered in clinical trial designs and data interpretation.

Fisiopatología de la ataxia de Friedreich: Transporte y degeneración axonal

Muñoz Lasso, DC. (2017). Fisiopatología de la ataxia de Friedreich: Transporte y degeneración axonal [Tesis doctoral no publicada]. Universitat Politècnica de València. doi:10.4995/Thesis/10251/92842

Friedreich ataxia (FRDA) is a recessive human disease of central and peripheral nervous system that affects children and young adults. FRDA is a peripheral neuropathy characterized by a initial degeneration of the large neurons of the dorsal root ganglia (DRG) or proprioceptive neurons. Most of the patients with FRDA have a homozygous guanine-adenine-adenine (GAA) expansion within the first intron of the gen that codifies for a small mitochondrial protein, frataxin (FXN). This mutation leads to a reduction of frataxin expression in all human cells, which produces changes in both the cell and mitochondrial physiology, resulting in a dysfunction of the mitochondrial energetic metabolism linked to the increase of oxidative stress and calcium dyshomeostasis. These cellular proceses are tightly related with the regulation of the actin and microtubule cytoskeletons and with vesicle trafficking. Here, we show how the absence of frataxin in the mouse models YG8R and YG8sR affects the axonal cytoskeleton of adult sensory neurons. Changes of actin and microtubule cytoskeletons and the failure of Ca 2+ signaling induce alterations of dynamics growth cones of sensory neurons, which in turn produce a reduction of their capacity to grow and regenerate their axons. This study shows how these events can lead to the neurodegeneration in Friedreich's ataxia.

Development of an iron-selective antioxidant probe with protective effects on neuronal function

García-Beltrán O, Mena NP, Aguirre P, Barriga-González G, Galdámez A, Nagles E, et al. (2017). PLoS ONE 12(12): e0189043. doi:10.1371/journal.pone.0189043

ron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinson´s and Alzheimer’s diseases, Friedreich ataxia and Huntington’s disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitro and in cells. CT51 bound Fe2+ with high selectivity and Fe3+ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe3+ to CT51, an important finding since stopping Fe2+/Fe3+ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation.

Health-related quality of life among adults with diverse rare disorders

Kathleen R. Bogart and Veronica L. Irvin; Orphanet Journal of Rare Diseases 201712:177 doi:10.1186/s13023-017-0730-1

Twenty-five to 30 million Americans live with a rare disease (RD) and share challenges unique to RD. The majority of research on RDs has focused on etiology, treatment and care, while the limited health-related quality of life (HRQL) research has been restricted to single RDs, small samples, or non-validated measures. This study reports HRQL among adults with diverse RDs, and compares their scores to those of the U.S. population and people with common chronic health conditions.

Biochemical Analyses of Human Iron–Sulfur Protein Biogenesis and of Related Diseases

Oliver Stehling, Viktoria D. Paul, Janina Bergmann, Somsuvro Basu, Roland Lill, Methods in Enzymology, Academic Press, ISSN 0076-6879, doi:10.1016/bs.mie.2017.11.004.

Maturation of Fe/S proteins in mammals is an intricate process mediated by two assembly systems located in the mitochondrial and cytosolic–nuclear compartments. Malfunction particularly of the mitochondrial system gives rise to severe neurological, metabolic, or hematological disorders, often with fatal outcome. In this chapter, we describe approaches for the differential biochemical investigation of cellular Fe/S protein maturation in mitochondria, cytosol, and nucleus. The analyses may also facilitate the identification of the affected Fe/S protein assembly step in diseased state. As Fe/S cluster insertion into target apoproteins is a frequent determinant of protein stability, examination of protein steady-state levels in biological samples frequently permits reliable first clues about the maturation process. In some specific cases, this approach allows the assessment of enzymatic or regulatory functions of Fe/S proteins, including the formation of lipoate cofactor by mitochondrial lipoic acid synthase or the posttranscriptional regulation of transferrin receptor and ferritin expression by the cytosolic iron regulatory proteins. More direct Fe/S protein maturation assays like enzymatic analyses may further validate the observed maturation defects. Here, we present a simple protocol for the determination of dihydropyrimidine dehydrogenase enzyme activity by thin-layer chromatography. In order to directly monitor Fe/S cluster insertion into target apoproteins, we have developed a 55Fe radiolabeling technique tracing the in vivo Fe/S cofactor formation in mammalian tissue culture. The combination of the presented techniques represents a comprehensive strategy to assess the multiple facets of Fe/S protein assembly for both mechanistic analyses and for the elucidation of specific defects in Fe/S diseases.

Computational drug repositioning for rare diseases in the era of precision medicine

Brian Delavan, Ruth Roberts, Ruili Huang, Wenjun Bao, Weida Tong, Zhichao Liu, Drug Discovery Today, 2017, , ISSN 1359-6446, doi:10.1016/j.drudis.2017.10.009.

There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases. First, we summarize the current genome landscape of rare diseases. Second, we propose several promising bioinformatics approaches and pipelines for computational drug repositioning for rare diseases. Finally, we discuss recent regulatory incentives and other enablers in rare disease drug development and outline the remaining challenges.

Depressive symptoms in Friedreich ataxia

Antonieta Nieto, Atteneri Hernández-Torres, Javier Pérez-Flores, Fernando Montón, International Journal of Clinical and Health Psychology, Available online 8 December 2017, ISSN 1697-2600, doi:10.1016/j.ijchp.2017.11.004.

Almost no attention has been paid to depression in Friedreich ataxia (FRDA), a highly disabling cerebellar degenerative disease. Our aim was to study the presence and the profile of depressive symptoms in FRDA and their relationship with demographic-disease variables and cognitive processing speed. Method: The study groups consisted of 57 patients with a diagnosis of FRDA. The Beck Depression Inventory-II was used to assess symptoms of depression. Speed of information processing was measured with a Choice Reaction time task. The mean BDI score for patients was significantly higher than the mean score in the general population. Twenty one percent of participants scored in the moderate/severe range. A Cognitive-Affective score and a Somatic-Motivational score was calculated for each patient. Patients’ scores in both dimensions were significantly higher than the scores in the general population. Demographic and disease variables were not related with symptoms of depression, except for severity of ataxia. Depressive symptoms predict cognitive reaction times. The greater proportion of variance was explained by the Cognitive-Affective dimension. Our data show that both somatic-motivational and cognitive affective symptoms of depression are frequent in individuals with FRDA. In addition, depressive symptoms may influence cognition, especially, the cognitive and affective symptoms.

Mitochondrial pore opening and loss of Ca2 + exchanger NCLX levels occur after frataxin depletion

R. Purroy, E. Britti, F. Delaspre, J. Tamarit, J. Ros, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Available online 6 December 2017, ISSN 0925-4439, doi:10.1016/j.bbadis.2017.12.005.

Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neurons survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons. In cardiomyocytes, frataxin depletion also results in mitochondrial permeability transition pore opening. Since the pore opening can be inhibited by cyclosporin A, we show that this treatment reduces lipid droplets and mitochondrial swelling in cardiomyocytes, restores DRG neuron survival and inhibits NFAT dephosphorylation. These results highlight the importance of calcium homeostasis and that targeting mitochondrial pore by repurposing cyclosporin A, could be envisaged as a new strategy to treat the disease.

Friedreich ataxia: Clinical feature and electrophysiological symptoms

Oguri M. ; J Neurosci Rural Pract [serial online] 2017 [cited 2017 Dec 6];8:691-2. DOI: 10.4103/jnrp.jnrp_248_17

The ataxia is slowly progressive and involves the lower extremities to a greater degree than the upper extremities. In general, results of electrophysiologic studies including visual, auditory brainstem, and somatosensory-evoked potentials are often abnormal.

Iron-induced oligomerization of human FXN 81-210 and bacterial CyaY frataxin and the effect of iron chelators

Eva-Christina Ahlgren, Mostafa Fekry, Mathias Wiemann, Christopher A. Söderberg, Katja Bernfur, Olex Gakh, Morten Rasmussen, Peter Højrup, Cecilia Emanuelsson, Grazia Isaya, Salam Al-Karadaghi. PLoS ONE 12(12): e0188937. doi:10.1371/journal.pone.0188937

Patients suffering from the progressive neurodegenerative disease Friedreich’s ataxia have reduced expression levels of the protein frataxin. Three major isoforms of human frataxin have been identified, FXN42-210, FXN56-210 and FXN81-210, of which FXN81-210 is considered to be the mature form.

C-Path And FARA Announce Collaborative Data Aggregation Project For Friedreich’s Ataxia

Tucson, AZ, and Downingtown, PA — Dec. 4, 2017 — Critical Path Institute's (C-Path) Data Collaboration Center (DCC) and the Friedreich's Ataxia Research Alliance (FARA) have announced that they will work together to develop an aggregated database of clinical data for Friedreich's ataxia (FA). Use of this database will promote collaborative research to support the understanding of natural history, potential biomarkers, and potential clinical endpoints for patients with FA, which will help researchers develop more efficient clinical trial protocols to test new therapies more quickly and effectively.

The project will establish an integrated database of clinical data for FA that can be shared and utilized by existing FA researchers. It will enlist companies that have carried out clinical trials in FA to obtain contributions of clinical data, as well as sharing natural history data collected by FARA's collaborative clinical research network.

The role of oxidative stress in Friedreich's ataxia

Federica Lupoli, Tommaso Vannocci, Giovanni Longo, Neri Niccolai and Annalisa Pastore. FEBS Letters, DOI: 10.1002/1873-3468.12928

Friedreich's ataxia is an excellent paradigmatic example of a disease in which oxidative stress plays an important, albeit not completely understood, role. Friedreich's ataxia is a rare genetic neurodegenerative disease which involves partial silencing of frataxin, a small mitochondrial protein completely ignored before being linked to Friedreich's ataxia.

Peripheral nerve ultrasound in Friedreich ataxia

Mulroy, E., Pelosi, L., Leadbetter, R., Joshi, P., Rodrigues, M., Mossman, S., Kilfoyle, D. and Roxburgh, R. (2017). Muscle Nerve. doi: 10.1002/mus.26012

The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs.
Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role.

Synthetic transcription elongation factors license transcription across repressive chromatin

Graham S. Erwin, Matthew P. Grieshop, Asfa Ali, Jun Qi, Matthew Lawlor, Deepak Kumar, Istaq Ahmad, Anna McNally, Natalia Teider, Katie Worringer, Rajeev Sivasankaran, Deeba N. Syed, Asuka Eguchi, Md. Ashraf, Justin Jeffery, Mousheng Xu, Paul M. C. Park, Hasan Mukhtar, Achal K. Srivastava, Mohammed Faruq, James E. Bradner, Aseem Z. Ansari; Science 30 Nov 2017 eaan6414, Published Online 30 Nov 2017 DOI: 10.1126/science.aan6414

The molecule being tested is designed to assist the enzyme that reads, or “transcribes,” DNA at the confusing repeats. Once it reaches the other side, the enzyme, called RNA polymerase, reads the gene and makes RNA that in turn codes for frataxin, the protein that is lacking in Friedreich’s ataxia.

Designer molecule points to treatment for diseases caused by DNA repeats

University of Wisconsin–Madison news, November 30, 2017 By David Tenenbaum.


Using a molecule designed to overcome a roadblock formed by a common type of genetic flaw, researchers at the University of Wisconsin–Madison have made progress towards novel molecular treatments for Friedreich’s ataxia — a rare but fatal disorder — in the laboratory dish and in animals.

Physical activity in the prevention of human diseases: role of epigenetic modifications

Elisa Grazioli, Ivan Dimauro, Neri Mercatelli, Guan Wang, Yannis Pitsiladis, Luigi Di Luigi and Daniela Caporossi; BMC Genomics 201718 (Suppl 8):802, doi:10.1186/s12864-017-4193-5

This review highlights the most significant findings from epigenetic studies involving physical activity/exercise interventions known to benefit chronic diseases such as metabolic syndrome, diabetes, cancer, cardiovascular and neurodegenerative diseases.

In conclusion, PA promises to be an important tool to be used alone or in combination with traditional therapies to improve the efficacy of strategies for disease prevention and treatment based on epigenetic modification. In this context, exercise remains an essential factor promoting important biological adaptations with profound implications for public health. Future collaborative studies may identify epigenetic markers with translational significance in identifying individuals for whom a personalized exercise regime could significantly alter the epigenomic signature and thus the risk of disease development or progression.

Differentially Regulated Cell-Free MicroRNAs in the Plasma of Friedreich's Ataxia Patients and Their Association with Disease Pathology

Subrahamanyam Dantham, Achal K. Srivastava, Sheffali Gulati, Moganty R. Rajeswari; Neuropediatrics 2017 Nov 27. DOI: 10.1055/s-0037-1607279

Friedreich's ataxia (FRDA) is a multisystem disease affecting the predominately nervous system, followed by muscle, heart, and pancreas. Current research focused on therapeutic interventions aimed at molecular amelioration, but there are no reliable noninvasive signatures available to understand disease pathogenesis. The present study investigates the alterations of plasma cell-free microRNAs (miRNAs) in FRDA patients and attempts to find the significance in relevance with the pathogenesis. Total RNA from the plasma of patients and healthy controls were subjected to miRNA microarray analysis using Agilent Technologies microarray platform. Differentially regulated miRNAs were validated by SYBR-green real-time polymerase chain reaction (Thermo Fisher Scientific). The study identified 20 deregulated miRNAs (false discovery rate < 0.01, fold change ≥ 2.0 ≤) in comparison with healthy controls; out of which 17 miRNAs were upregulated, and 3 miRNAs were downregulated. Target and pathway analysis of these miRNAs have shown association with neurodegenerative and other clinical features in FRDA. Further validation (n = 21) identified a set of significant (p < 0.05) deregulated miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223–3p, hsa-24–3p, and hsa-miR-21–5p in comparison with healthy controls. These miRNAs were reported to influence various pathological features associated with FRDA. The present study is expected to aid in the understanding of disease pathogenesis.

Do whole body vibration exercises affect lower limbs neuromuscular activity in populations with a medical condition? A systematic review

Dionello, Carla Fontouraa; de Souza, Patrícia Lopesa; Sá-Caputo, Danubiaa; Morel, Danielle Soaresa; Moreira-Marconi, Eloáb; Paineiras-Domingos, Laisa Lianea; Frederico, Eric Heleno Freire Ferreirab; Guedes-Aguiar, Elianeb; Paiva, Patricia de Castrob; Taiar, Redhah | Chiementin, Xavierh; Marín, Pedro J.i; Bernardo-Filho, Mariob; Restorative Neurology and Neuroscience, vol. 35, no. 6, pp. 667-681, 2017 DOI:10.3233/RNN-170765

The use of surface electromyography (sEMG) to evaluate muscle activation when executing whole body vibration exercises (WBVE) in studies provide neuromuscular findings, in healthy and diseased populations. Objectives:Perform a systematic review of the effects of WBVE by sEMG of lower limbs in non-healthy populations.
The group of Herrero evaluated muscle activation during WBVE of FA patients. The protocol consisted of two familiarization sessions and one working session that comprised six bouts of 3 min WBVE treatments on a tilt-table.

Patients organizations and new drug approval in the US. Eteplirsen and Duchenne muscular dystrophy case

Dal-Ré R, Lopez de Munain A, Ayuso C; Rev Neurol. 2017 Oct 16;65(8):373-380. [Article in Spanish]

INTRODUCTION:

In 2016 the US Food and Drug Administration (FDA) granted the marketing authorization for eteplirsen for Duchenne muscular dystrophy. This has been a very controversial decision since it happened after a negative assessment from both the Advisory Committee and the technical FDA evaluation team. The FDA's Center for Drug Evaluation and Research (CDER) director was who ultimately approved the product, while the FDA Commissioner did not overrule that decision.
AIM:

To report about the most relevant events regarding the approval of eteplirsen by the US FDA.
DEVELOPMENT:

All relevant facts that occurred during the clinical development and evaluation phase following 'accelerated approval' procedure of eteplirsen are discussed in detail. The technical FDA evaluation team reasons supporting that the drug has not proven clinical benefit, the attitude of patient advocacy groups and the post-approval FDA requirements to the marketing authorization holder are discussed. Finally, we reflect on what is the situation Spanish patients face once eteplirsen is on the US market.
CONCLUSIONS:

This is a unique case in the history of drug authorizations in western countries, that shows the difficulties that current regulations on accelerated approval of new medicines could have when interpreting scarce and low quality clinical development data, when dealing with rare diseases with no available therapies.

Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor.

Amelie Hu, Myriam Rai, Simona Donatello, Massimo Pandolfo; bioRxiv 221242; doi:10.1101/221242 (This article is a preprint and has not been peer-reviewed)
We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.

Voyager Therapeutics "update"

CAMBRIDGE, Mass., Nov. 16, 2017 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases, today at its R&D Day highlighted recent progress and plans for VY-AADC for advanced Parkinson’s disease, and progress with testing novel adeno-associated virus (AAV) capsids and delivery optimization efforts, along with its ALS, Huntington’s disease, Friedreich’s ataxia, anti-Tau antibody and severe chronic pain preclinical programs.

"Preclinical data from its Friedreich’s ataxia (FA) program in a transgenic mouse model of FA, with a one-time intravenous (IV) dosing of an AAV vector composed of a novel capsid and a frataxin transgene, together with intracerebral dosing of an AAV vector with the same transgene, that led to a rapid halting and reduction of FA disease progression in multiple functional tests of motor behavior. Additional preclinical studies are underway at Voyager including steps to identify a lead clinical candidate for the treatment of FA during 2018."

Proactive Ethical Design for Neuroengineering, Assistive and Rehabilitation Technologies: the Cybathlon Lesson

Marcello Ienca, Reto W. Kressig, Fabrice Jotterand and Bernice Elger; ournal of NeuroEngineering and Rehabilitation 201714:115 doi:10.1186/s12984-017-0325-z

As the fields of assistive technology and neuroengineering are entering a new phase of clinical and commercial maturity, there is an increasing need to address the ethical implications associated with the design and development of novel assistive and rehabilitative technological solutions. After reviewing various ethically-sensitive approaches to the design of NART, we proposed a framework for ethical design and development, which we call the Proactive Ethical Design (PED) framework. This framework is characterized by the convergence of user-centered and value-sensitive approaches to product design through a proactive mode of ethical evaluation. Four basic normative requirements are necessary for the realization of this framework: minimization of power imbalances, compliance with biomedical ethics, translationality and social awareness.

RESONANCIA MAGNÉTICA CARDIACA EN ATAXIA DE FRIEDREICH: SEGUIMIENTO CARDIACO DE LAS TERAPIAS ANTIOXIDANTES

Emilio Cuesta López. Tesis doctoral, UNIVERSIDAD AUTONOMA DE MADRID FACULTAD DE MEDICINA DEPARTAMENTO DE MEDICINA, Madrid 2017

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Hong Lin, Jordi Magrane, Amy Rattelle, Anna Stepanova, Alexander Galkin, Elisia M. Clark, Yi Na Dong, Sarah M. Halawani, David R. Lynch; Disease Models & Mechanisms 2017 10: 1343-1352; doi: 10.1242/dmm.030502

Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.

Insights on the conformational dynamics of human frataxin through modifications of loop-1

Martín E. Noguera, Martín Aran, Clara Smal, Diego S. Vazquez, María Georgina Herrera, Ernesto A. Roman, Nadine Alaimo, Mariana Gallo, Javier Santos; Archives of Biochemistry and Biophysics, Available online 31 October 2017, ISSN 0003-9861, doi:10.1016/j.abb.2017.10.022.

Human frataxin (FXN) is a highly conserved mitochondrial protein involved in iron homeostasis and activation of the iron-sulfur cluster assembly. FXN deficiency causes the neurodegenerative disease Friedreich's Ataxia. Here, we investigated the effect of alterations in loop-1, a stretch presumably essential for FXN function, on the conformational stability and dynamics of the native state. We generated four loop-1 variants, carrying substitutions, insertions and deletions. All of them were stable and well-folded proteins. Fast local motions (ps-ns) and slower long-range conformational dynamics (μs-ms) were altered in some mutants as judged by NMR. Particularly, loop-1 modifications impact on the dynamics of a distant region that includes residues from the β-sheet, helix α1 and the C-terminal. Remarkably, all the mutants retain the ability to activate cysteine desulfurase, even when two of them exhibit a strong decrease in iron binding, revealing a differential sensitivity of these functional features to loop-1 perturbation. Consequently, we found that even for a small and relatively rigid protein, engineering a loop segment enables to alter conformational dynamics through a long-range effect, preserving the native-state structure and important aspects of function.

Teaching Video NeuroImages: Spastic ataxia syndrome: The Friedreich-like phenotype of ARSACS

Saffie P, Kauffman MA, Fernandez JM, Acosta I, Espay AJ, de la Cerda A.;  Neurology. 2017 Oct;89(14) e178-e179. doi:10.1212/wnl.0000000000004556. PMID: 28972115.

ARSACS is the second most common cause of autosomal recessive spastic ataxia syndrome (SACS mutations account for 37% of Friedreich-negative cases)1 and should be considered in any population with suggestive MRI abnormalities.

BioWatch Thoughts on BioMarin's Q3-2017 Update

BioPortfolio, 30 Oct 2017 | Biotech Watcher

BMN-290 to Treat Friedreich’s Ataxia (FA)

BioMarin announced that it is advancing BMN-290 into clinical development to treat Friedreich’s Ataxia. This is a single gene disorder involving mutations in the FXN gene. This results in progressive loss of motor functions, as well as sensory impairments (i.e. vision, hearing, speech). The cognitive functions remain intact. The median age of death is around 35.

There are no FDA approved therapies. While there are “nuanced” results, the FA area clearly needs a more efficacious therapeutic in the clinical pipeline. Although BioMarin’s approach appears promising, we will reserve commentary until after the Phase 1 program is completed.

Drugs in Phase II/III Clinical Development, Friedreich’s Ataxia, October 2017

Omaveloxone (Omav), Reata Pharma (RETA), Phase 2, Nrf-2 upregulator & NF-kB inhibitor. Omav finished Part 1 of the MOXIe trial with mixed or nuanced results. 172 patient trial slated for top-line results in Q1-2020 and ongoing results until Q4-2022.

TAK-831, Takeda, Phase 2, 65 patient trial with completion slated for Q1-2019.

EPI-743, BioElectron, Phase 2, Testing patients with severe mitochondrial respiratory chain diseases who are considered to be within 90 days of end-of-life care. This includes FA patients

Milestones:
BMN-290 – Friedreich’s Ataxia
Small study involving chromatin modulation therapy shows promise. BMN-290 provides chromatin modulation therapy which appears more appropriate for long-term, chronic therapy. There is no disease-modifying therapy.

BMN-290 is a selective HDAC3 inhibitor of isoform 3, designed to inhibit histone deactylase enzymes. It helps unfold the chromatin structure to allow increased expression, Phase 1 - Safety Launch Q4-2017

Personality and Neuropsychological Profiles in Friedreich Ataxia

Sabrina Sayah, Jean-Yves Rotgé, Hélène Francisque, Marcela Gargiulo, Virginie Czernecki, Damian Justo, Khadija Lahlou-Laforet, Valérie Hahn, Massimo Pandolfo, Antoine Pelissolo, Philippe Fossati, Alexandra Durr; Cerebellum (2017). doi:10.1007/s12311-017-0890-5

We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Visual reasoning, memory, and learning were preserved. Emotional processes and social cognition were unimpaired. We also detected a change in automatic processes, such as reading. Personality traits were characterized by high persistence and low self-transcendence. The mild cognitive impairment observed may be a developmental rather than degenerative problem, due to early cerebellum dysfunction, with the impairment of cognitive and emotional processing. Disease manifestations at crucial times for personality development may also have an important impact on personality traits.

First Gene Therapy Treatment Candidate to Receive Orphan Designation in EU and USA

Agilis Biotherapeutics Announces Orphan Product Designation Approval in Europe for the Treatment of Friedreich Ataxia.

CAMBRIDGE, Mass.--(BUSINESS WIRE), October 31, 2017; Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the European Commission (EC) has granted Orphan Medicinal Product (OMP) designation in the European Union (EU) to the Company’s gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich ataxia (FA), an inherited degenerative neuromuscular disorder resulting in loss of motor coordination and strength, hearing, vision, speech and often premature death. The EC’s approval follows a positive opinion in July 2017 from the European Medicine Agency’s (EMA) Committee for Orphan Medicinal Products (COMP). This follows the Orphan Drug Designation for AGIL-FA granted by the U.S. Food and Drug Administration (FDA) last year.

Gene therapy—from small beginnings to where we are now

J C Glorioso and N Lemoine; Gene Therapy (2017) 24, 495–496; doi:10.1038/gt.2017.23

While there have been many hurdles to overcome that relate to safety, immunity and manufacturing, still, the logic of this treatment modality remains intact and most of us in the field believe that it will take its place as a standard of care just as the use of monoclonal antibodies and pharmaceutical drugs of all types has become widely employed. This is especially true for diseases that are too complex to treat with single approaches, such as cancer.
GT is one of the most highly regulated therapeutic fields. There were numerous control bodies formed to understand the long-term impact of gene therapy and to consider the dangers of viral vector engineering and transfer to humans. While the risk inherent in GT success is quite high, the rewards are potentially enormous both from a commercial as well as human medicine point of view.
There are many fields such as organ transplantation technology that have taken many years to develop before they have become standard practice, and no doubt gene therapy will take a similar path. We predict that by mid-century, there will be many GT options for patients, and in combination with other treatment strategies, will move human medicine to reach heights that are currently unanticipated. The challenge will be how to deliver what are now expensive and difficult treatments to people worldwide who have less developed health care systems and wealth. Our sense is that as we create better treatment options, their costs will come down and rival immunization protocols.

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

Celine J. Rocca, Spencer M. Goodman, Jennifer N. Dulin, Joseph H. Haquang, Ilya Gertsman, Jordan Blondelle, Janell L. M. Smith, Charles J. Heyser and Stephanie Cherqui; Science Translational Medicine 25 Oct 2017: Vol. 9, Issue 413, eaaj2347 DOI: 10.1126/scitranslmed.aaj2347

We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA.

Can rehabilitation improve the health and well-being in Friedreich’s ataxia: a randomized controlled trial?

Milne SC, Corben LA, Roberts M, Murphy A, Tai G, Georgiou-Karistianis N, Yiu EM, Delatycki MB; Clin Rehabil. 2017 Oct 1:269215517736903. doi: 10.1177/0269215517736903.

Our study indicates that rehabilitation can improve health and well-being in individuals with Friedreich’s ataxia; however, a larger study is required to have sufficient power to detect a significant change in the most sensitive measure of function, the motor domain of the Functional Independence Measure.

Reata Announces First Patient Enrolled in Part 2 of MOXIe Study of Omaveloxolone for the Treatment of Friedreich’s Ataxia

IRVING, Texas, Oct. 23, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (NASDAQ:RETA) (“Reata” or the “Company”) today announced the enrollment of the first patient in the pivotal Part 2 of the MOXIe trial to evaluate omaveloxolone in patients with Friedreich’s ataxia (FA).
Part 2 of the MOXIe trial is a double-blind, randomized, placebo-controlled, multi-center, international trial designed to evaluate the safety, tolerability, and efficacy of omaveloxolone in patients with FA. The trial will enroll approximately 100 FA patients randomized evenly to either 150 mg of omaveloxolone or placebo. The primary endpoint of the trial will be the change from baseline in the modified Friedreich’s Ataxia Rating Scale (mFARS) of omaveloxolone compared to placebo at 48 weeks. Additional endpoints will include the change from baseline in peak work during maximal exercise testing, Patient Global Impression of Change, and Clinical Global Impression of Change. The U.S. Food and Drug Administration has confirmed that use of mFARS as the primary endpoint in Part 2 of the MOXIe trial can support approval of omaveloxolone in FA. Reata expects top-line data to be available in the second half of 2019.

Friedreich’s ataxia: clinical features, pathogenesis and management

A Cook, P Giunti; British Medical Bulletin,  2017, 1–12 doi:10.1093/bmb/ldx034

The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets.
The search for effective disease-modifying agents continues. It remains to be determined whether the most effective approach to treatment lies with increasing frataxin protein levels or addressing the metabolic consequences of the disease, for example with antioxidants.
Management of Freidreich’s ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential.

Incidence et caractéristiques de la scoliose neurologique dans l’ataxie de Friedreich à maturité osseuse

Jean Meyblum, Anne-Laure Simon, Christophe Vidal, Isabelle Husson, Bastien Roche, Brice Ilharreborde, Revue de Chirurgie Orthopédique et Traumatologique, Volume 103, Issue 7, Supplement, November 2017, Page S52, ISSN 1877-0517, doi:10.1016/j.rcot.2017.09.072.

L’incidence de la déformation scoliotique est élevée dans l’AF (74 % de la cohorte). Il n’existe pas de prévalence d’un type particulier de courbure. L’hypercyphose thoracique était fréquemment retrouvée sans être associée à un type de scoliose, témoignant du déséquilibre antérieur de la marche cérébelleuse. L’arthrodèse rachidienne n’a pas fait perdre la marche chez les patients marchant encore au moment de la chirurgie.

Cardiomyopathy in Friedreich’s Ataxia

Pablo Salazar, Raksha Indorkar, Michael Dietrich, Afshin Farzaneh-Far; European Heart Journal, , ehx607, doi:10.1093/eurheartj/ehx607

A 27-year old man with Friedreich’s Ataxia was referred for cardiac evaluation. He had no cardiac symptoms, and his physical exam was remarkable for an ataxic-gait and increased muscle tone.

Nrf2-Inducers Counteract Neurodegeneration in Frataxin-Silenced Motor Neurons: Disclosing New Therapeutic Targets for Friedreich’s Ataxia

Petrillo, S.; Piermarini, E.; Pastore, A.; Vasco, G.; Schirinzi, T.; Carrozzo, R.; Bertini, E.; Piemonte, F.; Int. J. Mol. Sci. 2017, 18, 2173. doi:10.3390/ijms18102173

In FA, the dys-regulation of cellular antioxidant defenses, due to frataxin deficiency, exacerbates oxidative stress, thus the Nrf2 activation becomes more and more of an attractive strategy for the treatment of this disease.

Overall, our findings support Nrf2 as a therapeutic target for FA, and its induction as a promising approach to prevent or slow the pathological changes observed in this disease. Furthermore, the Nrf2 impairment mirrored at the systemic level in PBMCs of patients may help to open new perspectives for biomarker research in FA, potentially useful for monitoring clinical trials.

Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV-1 vector

Maria Ventosa, Zetang Wu and Filip Lim; The Journal of Gene Medicine, Accepted manuscript online: 17 OCT 2017 08:40PM EST DOI: 10.1002/jgm.2993

With the aim of developing a gene therapy for FA neuropathology, here we describe the construction and preliminary characterization of a high capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B-FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1.

We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglion neurons with the H24B-FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B-FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month.

Our results support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy.

BioMarin Selects BMN 290 for Friedreich's Ataxia

SAN RAFAEL, Calif., Oct. 18, 2017 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) updated the investment community on the Company's development portfolio, which is focused on innovative therapies to treat rare and ultra-rare diseases.
BioMarin announced today that it has selected BMN 290, a selective chromatin modulation therapy, for the treatment of Friedreich's Ataxia (FA). FA is a rare autosomal recessive disorder with worldwide prevalence of approximately 15,000, which results in disabling neurologic and cardiac progressive decline. Currently there are no approved disease modifying therapies for FA. In preclinical models, BMN 290 increases frataxin expression in affected tissues more than two-fold. BMN 290 is a second generation compound derived from a compound acquired from Repligen that had human clinical data demonstrating increases in frataxin in FA patients. BMN 290 was selected for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. The company expects to submit the IND in 2H 2018.

New data for Friedreich's ataxia with a novel capsid demonstrate reversal of disease phenotype in a preclinical disease model.

Press Release: CAMBRIDGE, Mass., Oct. 17, 2017 (GLOBE NEWSWIRE) -- Voyager Therapeutics, Inc. (NASDAQ:VYGR), a clinical-stage gene therapy company focused on developing life-changing treatments for severe neurological diseases announced today multiple data presentations at the Congress of the European Society of Gene and Cell Therapy (ESGCT) taking place October 17-20, 2017, in Berlin, Germany. The data include an oral presentation related to recent results from Voyager's ongoing Phase 1b trial of VY-AADC01 in advanced Parkinson's disease, as well as six poster presentations related to Voyager's novel adeno-associated virus (AAV) capsid optimization efforts, gene therapy manufacturing, and preclinical pipeline programs.

Rescue of Central and Peripheral Neurological Phenotype in a Novel Mouse Model of Friedreich's Ataxia by Intravenous Delivery of AAV Frataxin." Poster P107.

Friedreich's ataxia is a severe, inherited neurological disease caused by mutations in the frataxin gene leading to decreased expression of frataxin (FXN), which results in severe sensory impairment, progressive loss of the ability to walk, generalized weakness, loss of sensation, as well as severe and potentially fatal cardiomyopathy. In a transgenic mouse model of FA, one-time intravenous post-symptomatic dosing of an AAV vector composed of a novel AAV capsid and a frataxin transgene, together with intracerebral dosing also delivering a frataxin transgene, rapidly halted and reduced FA disease progression in multiple tests including three functional tests of motor behavior and one electrophysiological test. In addition, increasing intravenous vector doses with the same novel capsid together with a fixed dose of the intracerebral vector led to a dose-dependent rescue of the FA phenotype. This novel AAV capsid provided at least 20-fold greater delivery of the vector to sensory ganglia as measured by vector genomes, and approximately a three-fold greater expression of frataxin in the cerebellum, as compared to an AAV9 vector at a similar dose. Additional preclinical studies are underway at Voyager including steps to optimize a lead clinical candidate for the treatment of FA.

New data for Friedreich's ataxia with a novel capsid demonstrate reversal of disease phenotype in a preclinical disease model.

Recombinant adeno-associated viral vector serotype 5 carrying the gene for the human frataxin protein for the treatment of Friedreich’s ataxia

EU/3/17/1906: Public summary of opinion on orphan designation (First published: 17/10/2017): On 23 August 2017, orphan designation (EU/3/17/1906) was granted by the European Commission to Voisin Consulting S.A.R.L., France, for recombinant adeno-associated viral vector serotype 5 carrying the gene for the human frataxin protein (also known as AGIL-FA) for the treatment of Friedreich’s ataxia.
What is the stage of development of this medicine?:
The effects of the medicine have been evaluated in experimental models.
At the time of submission of the application for orphan designation, no clinical trials with this medicinein patients with Friedreich’s ataxia had been started.
At the time of submission, the medicine was not authorised anywhere in the EU for Friedreich’s ataxia.
Orphan designation of the medicine had been granted in the United States for this condition.

Therapies for mitochondrial diseases and current clinical trials

Ayman W. El-Hattab, Ana Maria Zarante, Mohammed Almannai, Fernando Scaglia, In Molecular Genetics and Metabolism, 2017, , ISSN 1096-7192, doi:10.1016/j.ymgme.2017.09.009.

Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Based on limited number of clinical trials, several agents aiming at enhancing mitochondrial function or treating the consequences of mitochondrial dysfunction have been used. Several agents are currently being evaluated for mitochondrial diseases. Therapeutic strategies for mitochondrial diseases include the use of agents enhancing electron transfer chain function (coenzyme Q10, idebenone, riboflavin, dichloroacetate, and thiamine), agents acting as energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), amino acids restoring nitric oxide production (arginine and citrulline), cardiolipin protector (elamipretide), agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide bypass therapy, liver transplantation, and gene therapy. Although, there is a lack of curative therapies for mitochondrial disorders at the current time, the increased number of clinical research evaluating agents that target different aspects of mitochondrial dysfunction is promising and is expected to generate more therapeutic options for these diseases in the future.

In Vivo Assessment of Mitochondrial Dysfunction in Clinical Populations Using Near-Infrared Spectroscopy

T. Bradley Willingham and Kevin K. McCully, Front. Physiol., 14 September 2017 doi:10.3389/fphys.2017.00689

The ability to sustain submaximal exercise is largely dependent on the oxidative capacity of mitochondria within skeletal muscle, and impairments in oxidative metabolism have been implicated in many neurologic and cardiovascular pathologies. Here we review studies which have demonstrated the utility of Near-infrared spectroscopy (NIRS) as a method of evaluating of skeletal muscle mitochondrial dysfunction in clinical human populations.

In FRDA, NIRS measures of mitochondrial capacity in the forearm were inversely correlated with feelings of low energy, suggesting that mitochondrial function may be related to fatigue in persons with FRDA across the spectrum of symptom severity (Bossie et al., 2016). These findings lend support to the use of NIRS measures of mitochondrial capacity as measure of muscle dysfunction in persons with FRDA during interventions or over the course of disease progression.

There are currently no physiological evaluation tools available for clinicians diagnosing and treating patients with mitochondrial disease, and the application of NIRS may offer a relevant, in vivo measure of mitochondrial function in this population. To date, Friedreich's ataxia is the only mitochondrial disease to be evaluated using NIRS, and establishing the usefulness of NIRS in evaluating mitochondrial dysfunction in persons with mitochondrial disease warrants further investigation.

Estudos moleculares em ataxia de Friedreich

Peluzzo, Thiago Mazzo, Advisor: França Junior, Marcondes Cavalcante; TESE DIGITAL 2017

We therefore designed this study to determine the frequency, phenotypic and mutational profile of Brazilian patients that presented compound heterozygosity for FXN. To accomplish that, we recruited patients from 3 national reference centers (State University of Campinas-UNICAMP, São Paulo University at Ribeirão Preto-USP-RP and Federal University of Rio Grande do Sul-UFRGS). Those patients with a single identified expansion underwent sequencing of all 5 exons and exon-intron boundaries at FXN (Sanger technique). We identified a novel variant (c.482+1G>T) considered pathogenic following American College of Medical Genetics and Genomics (ACMG) guidelines. In addition, another pathogenic variant previously described in the literature (c.157delC) was found in 2 unrelated subjects. Compound heterozygosity accounted for 2.87% (5/174) of all patients; however, when considered only cases in which point mutations were found, the rate decreases to 1,72% (3/174). These are novel data for the Brazilian population. From a clinical perspective, they will help the choice of adequate techniques for FRDA diagnosis and proper genetic counseling in our country.

CRISPR Therapeutics Awarded Grant from Friedreich’s Ataxia Research Alliance to Collaborate with University of Alabama at Birmingham on Gene-edited Treatments for Friedrich’s Ataxia

ZUG, Switzerland and CAMBRIDGE, Mass., Oct. 13, 2017 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (NASDAQ:CRSP), a genome editing company focused on creating transformative medicine for serious diseases, today announced the receipt of the Kyle Bryant Translational Research Award from Friedreich’s Ataxia Research Alliance (FARA), a non-profit organization that is focused on curing Friedreich’s Ataxia (FA). The grant is awarded to fund research on in vivo CRISPR/Cas9-based gene-editing approaches to treat FA, which will be performed in collaboration with Dr. Marek Napierala at University of Alabama at Birmingham. This announcement coincides with FARA’s rideATAXIA Philadelphia event, a lead location in an annual bike ride program founded by patient Kyle Bryant, that increases FA awareness and raises funds to treat and cure FA through research.

FDA awards six grants for natural history studies in rare diseases

12-10-2017. SILVER SPRING, Md: The U.S. Food and Drug Administration today announced it has awarded six new research grants for natural history studies in rare diseases. The aim of the research is to inform medical product development by better understanding how specific rare diseases progress over time.
Grants being funded by the FDA:
•
•Children's Hospital of Philadelphia, David Lynch, Prospective study in Friedreich's ataxia, approximately $2 million over 5 years
•

Mathematical modeling of Friedreich’s ataxia – a genetic neuro-muscular degenerative condition

SWASTI WAGH and D.K. WAGH; Journal of Ultra Scientist of Physical Sciences, Volume 29, Issue 2, Page Number 66-70, 2017 doi:10.22147/jusps-A/290203

Currently Friedreich’s Ataxia (FA) is not considered an important health problem because of its relatively low prevalence in the general population. However with improvement in health care diagnosis and delivery provisions, more and more people with Friedreich’s Ataxia (FA) are being diagnosed and surviving. This means that its incidence and prevalence is bound to change. We have used a mathematical model to estimate generational increase in the number of patients and carriers with FA. The results portray a scary picture and hence demand measures to take it more seriously by health care providers.

Today Friedreich’s Ataxia is considered to be a rare disease. Being genetic it passes on in offspring. Calculations based on the Mathematical Model reveal that practically in the seventh generation almost 1/4th of the population becomes patient. This is very serious and to avoid this measures must be taken. On the basis of Mathematical Model we can suggest following measures. It follows from matrix B that if a carrier is crossed with the normal, the probability of offspring being patient is zero. Hence if the carrier is not allowed to cross with patient or the carrier the increase in population of patients can be controlled.

The New Zealand Neuromuscular Disease Patient Registry; Five Years and a Thousand Patients.

Rodrigues, Miriam J., O’Grady, Gina, Hammond-Tooke, Graemed, Kidd, Alexaf, Love, Donald O.g, Baker, Ronelle K.b, Roxburgh, Richard H.a; Journal of Neuromuscular Diseases, vol. 4, no. 3, pp. 183-188, 2017; DOI: 10.3233/JND-170240

The changing roles of a rare disease patient registry. (a) Ten roles performed by registries along the pathway of treatment development – adapted with permission from Betsy Bogard (see acknowledgements*). (b) The NZ NMD Registry’s current role in the pathway of treatment development for its respective patient populations.

We have demonstrated that an overarching registry serving all neuromuscular diseases managed by a single project team is effective; this is in contrast to countries such as the UK, Spain and Germany where disease-specific registries are commonly deployed but similar to Canada where the Canadian Neuromuscular Disease Registry (CNDR) covers a range of disorders

Friedreich Ataxia: Developmental Failure of the Dorsal Root Entry Zone

Arnulf H. Koeppen, MD Alyssa B. Becker, BA Jiang Qian, MD, PhD Benjamin B. Gelman, MD, PhD Joseph E. Mazurkiewicz, PhD; Journal of Neuropathology & Experimental Neurology, nlx087, doi:10.1093/jnen/nlx087

The transition between PNS and CNS myelin proteins was disorganized. During development, neural-crest derived boundary cap cells provide guidance to dorsal root ganglia axons growing into the dorsal spinal cord and at the same time block the inappropriate intrusion of CNS glia into DR. It is likely that frataxin is required during a critical period of permissive (axons) and nonpermissive (astroglia) border-control.

Agilis Biotherapeutics Updates on Progress in CNS Gene Therapy Programs

CAMBRIDGE, Mass.--(October 03, 2017)--Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS),

Friedreich Ataxia: The Company’s program in Friedreich ataxia (FA), AGIL-FA, an AAV-based vector for delivery of the human FXN gene intended to address the CNS manifestations of FA, is advancing rapidly through nonclinical, manufacturing and regulatory activities toward human clinical study. Agilis has generated a proprietary library of optimized FXN gene constructs through engineering of promotor and gene regulatory elements tied to the wild-type FXN gene in collaboration with Intrexon Corporation (NASDAQ: XON), resulting in novel compositions of matter and intellectual property. In vitro characterization, including analyses in inducible pluripotent stem cell systems, has verified the critical functional parameters of the optimized FXN gene and frataxin protein, leading to selection of the AGIL-FA lead construct. Analyses of routes of CNS administration and biodistribution of the optimized lead construct using the selected AAV vector have been completed in five in vivo IND-enabling non-clinical studies, demonstrating reproducible targeting of the FXN gene to, and expression of the frataxin protein in, target CNS cells that data suggest are integral to CNS manifestations in FA. The Company has completed a pre-IND meeting with the FDA and is on track to open an IND in 2018

Comprehensive Analysis of Gene Expression Patterns in Friedreich’s Ataxia Fibroblasts by RNA Sequencing Reveals Altered Levels of Protein Synthesis Factors and Solute Carriers

Napierala JS, Li Y, Lu Y, Lin K, Hauser LA, Lynch DR, Napierala M; University of Alabama at Birmingham, Accession: PRJNA412241, National Center for Biotechnology Information, GEO: the Gene Expression Omnibus. Public on Sep 27, 2017

We used RNA sequencing to profile the transcriptomes of primary fibroblast cell lines derived from 18 FRDA patients and 17 unaffected control individuals. Transcriptome profiling of FRDA skin fibroblasts revealed significantly upregulated expression of genes encoding plasma membrane solute carrier proteins. Conversely, the expression of genes encoding accessory factors and enzymes involved in cytoplasmic and mitochondrial protein synthesis was consistently decreased in the FRDA cells. Finally, comparison of genes differentially expressed in FRDA fibroblasts to 3 previously published gene expression signatures defined for FRDA blood cells showed substantial overlap between the independent datasets, including correspondingly deficient expression of antioxidant defense genes. Together, these results indicate that gene expression profiling of cells derived from peripheral tissues can, in fact, consistently reveal novel molecular pathways of the disease.

Frataxin-deficient neurons and mice models of Friedreich ataxia are improved by TAT-MTScs-FXN treatment

Elena Britti, Fabien Delaspre, Anat Feldman, Melissa Osborne, Hagar Greif, Jordi Tamarit, Joaquim Ros; J. Cell. Mol. Med. Vol XX, No X, 2017 pp. 1-15 doi: 10.1111/jcmm.13365

In mice models of the disease, administration of TAT-MTScs-FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT-MTScs-FXN as a treatment for Friedreich ataxia.

The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population

Jonathan F. Plehn, Keren Hasbani, Inez Ernst, Kenneth D. Horton, Bart E. Drinkard, Nicholas A. Di Prospero, Journal of Cardiac Failure, Available online 3 October 2017, ISSN 1071-9164, doi:10.1016/j.cardfail.2017.09.012.

A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.
In our pediatric cohort, GAA repeat length on either allele failed to correlate with LVMI or with measures of systolic or diastolic LV function. These findings are consistent with those of others, two or which were based on robust cMRI criteria. We did note a non-significant trend in GAA repeat length on the long allele with increasing categorical severity of LV remodeling. Despite the high prevalence of ventricular remodeling and functional associations described in this population, there is no evidence to date that early pharmacologic intervention can prevent or impede development of ventricular and/or clinical deterioration.

Urinary, bowel and sexual symptoms in a cohort of patients with Friedreich’s ataxia

Meher Lad, Michael H. Parkinson, Myriam Rai, Massimo Pandolfo, Petya Bogdanova-Mihaylova, Richard A. Walsh, Sinéad Murphy, Anton Emmanuel, Jalesh Panicker† and Paola Giunti; Orphanet Journal of Rare Diseases 201712:158 doi:10.1186/s13023-017-0709-y

Pelvic symptoms are distressing symptoms experienced by patients with Friedreich’s Ataxia (FRDA). The aim of this study was to describe the prevalence of lower urinary tract symptoms (LUTS), bowel and sexual symptoms in FRDA.
A high proportion of FRDA have symptoms suggestive of LUTS, bowel and sexual dysfunction. This is more marked with greater disease duration and later disease onset. These symptoms need to be addressed by clinicians as they can have a detrimental effect on patients.

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Brian Feingold, William T. Mahle, Scott Auerbach, Paula Clemens, Andrea A. Domenighetti, John L. Jefferies, Daniel P. Judge, Ashwin K. Lal, Larry W. Markham, W. James Parks, Takeshi Tsuda, Paul J. Wang, Shi-Joon Yoo
and On behalf of the American Heart Association Pediatric Heart Failure Committee of the Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Stroke Council; Circulation. 2017;136:e200-e231 doi:10.1161/CIR.0000000000000526

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions.
Cardiac manifestations consist of LV hypertrophy with fibrosis and scarring, arrhythmias, and progressive HF. Cardiac dysfunction is the most frequent cause of death in FA.
Because no relationship between severity of cardiac involvement and neurological status has been identified, regular cardiac evaluation regardless of neurological status is likely warranted.

Diabetes mellitus as the presenting feature of Friedreich's ataxia

Garg M, Kulkarni SD, Shah KN, Hegde AU. J Neurosci Rural Pract 2017;8, Suppl S1:117-9 DOI: 10.4103/jnrp.jnrp_112_17

This is an unusual report of diabetes as the initial presentation in a patient with FA. This patient has also shown accelerated course of disease. However, the genetic mechanisms accounting for phenotypic variations in FA remain to be fully elucidated. In patients with diabetes who present with early sensory neuropathy or ataxia, FA should be a consideration even in the pediatric age group. A better understanding of molecular mechanisms will certainly pave the way for improved therapeutic strategies in the near future.

Lipophilic methylene violet analogues as modulators of mitochondrial function and dysfunction

Sandipan Roy Chowdhury, Omar M. Khdour, Indrajit Bandyopadhyay, Sidney M. Hecht. In Bioorganic & Medicinal Chemistry, 2017,ISSN 0968-0896, doi:10.1016/j.bmc.2017.08.021.

The methylene violet analogues were evaluated for their ability to preserve mitochondrial function in Friedreich’s ataxia (FRDA) lymphocytes. The analogues were shown to be efficient ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I. The analogues also preserved mitochondrial membrane potential and augmented ATP production. The analogues were found to be better antioxidants than the parent compounds methylene blue and methylene violet.

Keywords: Methylene blue; Methylene violet; Mitochondria; Reactive oxygen species; Friedreich’s ataxia; Cytoprotection

Manuela Corti, assistant professor in the department of pediatrics at the University of Florida in Gainesville, was awarded an MDA research grant totaling $298,954 over three years to study gene therapy in Friedreich’s ataxia (FA).

Source: MDA.org, 09/21/2017.

Our objective is to develop a treatment strategy for FA, one of the most common forms of ataxia. Specifically, our research plan focuses on the correction of both the cardiac and neurological degeneration found in the disease. These changes are due to harmful changes in the frataxin gene.
This work will specifically answer important mechanistic questions in a new FA mouse model, which has many of the symptoms of the human patients. First, we will identify the best route of delivery for the frataxin gene in the nervous system by comparing three different strategies for injecting the vector (delivery vehicle). Second, we will test the safety of repeated delivery of the frataxin gene vector in combination with medications that will prevent reactions against the frataxin protein and the vector components. Completion of this project will be an important milestone in the development of a treatment strategy that will dramatically improve quality of life for FA patients.

Bioavailability of resveratrol: Possibilities for enhancement

Konrad de Vries, Morné Strydom, Vanessa Steenkamp, Journal of Herbal Medicine, Available online 12 September 2017, ISSN 2210-8033, doi:10.1016/j.hermed.2017.09.002.

Resveratrol is a naturally occurring polyphenol that has been shown to elicit a variety of beneficial effects in vitro. Translating these gains to in vivo and clinical settings has proven to be a major challenge, because of its poor oral bioavailability. This caveat was confirmed after reviewing clinical trials conducted on this investigational product over the past two years. This review provides alternative methods of administration of resveratrol which may enhance its bioavailability. However, these methods: remain to be validated.
From current literature, it is clear that orally administered resveratrol has low bioavailability in vivo. A variety of methods that could overcome the inherent issues with resveratrol bioavailability have been proposed, however these need to be further validated in order to determine which are safe, effective and superior to traditional oral administration of resveratrol before clinical evaluation can take place.

Friedreich Ataxia: Treatment with Genetic Approach

Martin L. Nelwan, Journal of Advances in Biology & Biotechnology, 2394-1081,Vol.: 14, Issue.: 4

Adequate treatments are unavailable for this disorder at present. However, to treat FA, genetic approach can be used. The approach may comprise genetic counseling and use of advanced therapy, gene therapy for instance. 

Molecular Alterations in a Mouse Cardiac Model of Friedreich’s Ataxia: An Impaired Nrf2 Response Mediated via Up-Regulation of Keap1 and Activation of the Gsk3β Axis

Amy Anzovino, Shannon Chiang, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang, The American Journal of Pathology, Available online 19 September 2017, ISSN 0002-9440,  doi:10.1016/j.ajpath.2017.08.021.

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich’s ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms.
Collectively, cardiac frataxin-deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Keap1, and activation of Gsk3β-signaling that decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.

Movement disorders hidden in the neuromuscular clinic

J. Reimann, S. Paus, Neuromuscular Disorders, Volume 27, Supplement 2, October 2017, Page S243, ISSN 0960-8966, doi:10.1016/j.nmd.2017.06.531.

We present these exemplary cases to increase awareness of these disorders and the differential diagnosis for those working in neuromuscular clinics, as well as an incentive for more interaction with the movement disorder field, in particular when struggling to define a diagnosis. We also observe a number of referrals that turn out to be movement disorders. In some, this is caused by known neuromuscular manifestations while missing the CNS signs. Examples are our cases of Huntington’s disease presenting with weakness, pain and atrophy of the calves and of Friedreich ataxia send for work-up of sensory axonal neuropathy and scoliosis, where “restlessness” and “nasal speech”, respectively, were ignored as symptoms. In others, the attribution of the pathophysiology to muscle is simply wrong.

Relationship Between Neurological Disability and Visual Impairment in Patients With ALS or Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT03285204, First received: March 8, 2017
Principal Investigator: Jose L Urcelay, PhD HGU Gregorio Marañón.
Location: Madrid, Spain,

The aim of this study is to obtain an early biomarker of amyotrophic lateral sclerosis and Friedreich's Ataxia which allows to diagnose the disease in an initial stage and to follow up the patient with optic coherence tomography, a fast, non-invasive and comfortable method.

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Shao-Hua Yang, Wenjun Li, Nathalie Sumien, Michael Forster, James W. Simpkins, Ran Liu, In Progress in Neurobiology, Volume 157, 2017, Pages 273-291, ISSN 0301-0082, doi:10.1016/j.pneurobio.2015.10.005.

Highlights:
Reprogramming energetic metabolism is a common feature for neurodegenerative diseases and cancers.
Methylene blue functions as an alternative mitochondrial electron transfer carrier, enhancing bioenergetics and inhibiting biosynthetics.
Methylene blue provides protective effect in rodent models of Parkinson disease, Alzheimer's disease, Huntington's disease, and Friedreich's ataxia.
Methylene blue reverses Warburg's effect and inhibits cancers proliferation.
Alternative mitochondrial electron transfer may provide a common novel therapeutic mechanism for cancers and neurodegenerative diseases.

Market access of Spinraza (Nusinersen) for spinal muscular atrophy: intellectual property rights, pricing, value and coverage considerations

S Simoens and I Huys; Gene Therapy , (7 September 2017) | doi:10.1038/gt.2017.79

In December 2016, Spinraza (Nusinersen), Biogen (Durham, NC, USA) was the first treatment to be registered as an orphan drug by the US Food and Drug Administration for SMA. In Europe, a gene therapy in principle classifies as an Advanced Therapy Medicinal Product (ATMP), covered by a regulatory framework with particular incentives for drug developers. For Nusinersen, the European Medicines Agency recently granted the Accelerated Assessment status in 2016. With respect to its price, it has been reported that the annual wholesale costs of treating a patient with Nusinersen will amount to $750 000 for the first year and $375 000 for subsequent years. Biogen argues that this price is in line with that of other orphan drugs for rare diseases.
Despite marketing authorization of Nusinersen in the United States and in Europe, patient access to this new promising therapy remains uncertain. The price of this new drug clearly triggers several questions in terms of justification, transparency and responsibility.
The aim of this Comment is to identify and to discuss issues related to the market access of Nusinersen for SMA by focusing specifically on intellectual property rights, pricing, value and coverage considerations from the perspective of the company, patients and society.
The pricing of Nusinersen is a black box, although Biogen claims that the price of Nusinersen is in line with its clinical benefit and with prices of other orphan drugs. Any data about the value assessment of Nusinersen is not (publicly)available. This asymmetry (or even absence) of information between Biogen and insurers needs to be tackled in an era when insurers (and society at large) need to make and justify difficult choices. A quantifiable and evidence-driven approach to pricing and value assessment is required and such data need to be available to the stakeholders involved.

Detection of long repeat expansions from PCR-free whole-genome sequence data

Egor Dolzhenko, Joke J.F.A. van Vugt, Richard J. Shaw, Mitchell A. Bekritsky, Marka van Blitterswijk, Giuseppe Narzisi, Subramanian S. Ajay, Vani Rajan, Bryan Lajoie, Nathan H. Johnson, Zoya Kingsbury, Sean J. Humphray, Raymond D. Schellevis, William J. Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H.P. Tazelaar, Michael A. van Es, Russell McLaughlin, William Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-Chalabi, Chris Shaw, Bradley Smith, Edmund J. Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S. Wexler, The US-Venezuela Collaborative Research Group, David E. Housman, Christopher W. Ng, Alina L. Li, Ryan J. Taft, Leonard H. van den Berg, David R. Bentley, Jan H. Veldink, and Michael A. Eberle. Genome Res. gr. 225672.117 Published in Advance September 8, 2017, doi:10.1101/gr.225672.117

We further applied our algorithm to a set of 152 samples where every sample had one of eight different pathogenic repeat expansions including those associated with fragile X syndrome, Friedreich's ataxia and Huntington's disease and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions. The software is licensed under GPL v3.0 and the source code is freely available on GitHub.

Nitric oxide prevents Aft1 activation and metabolic remodeling in Frataxin-deficient yeast

David Alsina, Joaquim Ros, Jordi Tamarit, Redox Biology, Available online 6 September 2017, ISSN 2213-2317, doi:10.1016/j.redox.2017.09.001.






A major conclusion of this work is that Yfh1 deficiency activates the iron regulon by a different pathway than iron-sulfur loss. Therefore, alternative pathways for Aft1 activation may exist in yeast which, as discussed above, could be related to the presence of anomalous iron species. We have also observed that metabolic status can be efficiently monitored using a targeted proteomics strategy focusing on key metabolic enzymes. Finally, the observation that NO can mitigate the defects caused by Yfh1 deficiency supports the hypothesis that Yfh1 loss leads to the increased presence of anomalous iron forms, and that this anomalous iron plays a central role in the events caused by Yfh1 deficiency. It also suggests that NO donors could have a therapeutic effect in FRDA patients. NO donors such as SNP or nitroglycerin have been used for more than a century for controlling congestive heart failure associated with heart attack or lowering blood pressure during surgery. Beyond its vasodilating action, neuroprotective properties have been demonstrated for NO in an iron-induced model of Parkinson's disease. This observation, together with the results presented in this work, opens the possibility to explore the potential therapeutic effect of NO donors in mammalian models of FRDA.

RNA biology of disease-associated microsatellite repeat expansions

Kushal J. Rohilla and Keith T. Gagnon, Acta Neuropathologica 20175:63, doi:10.1186/s40478-017-0468-y

This review focuses on the potential impact that simple tandem repeat expansions can have on the biology and metabolism of RNA that contain them and underscores important gaps in understanding. Merging the molecular biology of repeat expansion disorders with the current understanding of RNA biology, including splicing, transcription, transport, turnover and translation, will help clarify mechanisms of disease and improve therapeutic development.
Repeat expansion sequences are known to inhibit or impede RNA Polymerase II (Pol II) initiation or elongation either directly or via induction of a repressed chromatin state. Expansions like the GAA repeat in FRDA have been implicated in reduced or silenced transcription.
Examples of microsatellite repeat expansions modulating splicing include the GAA repeat expansion associated with FRDA. When placed near reporter gene exons or in the first intron of a frataxin minigene system, the GAA repeat caused complex splicing defects and accumulation of aberrant splice products. The mechanism proposed involved binding of various splicing factors to the GAA repeat-containing transcripts.
Therapeutic approaches to control xtrRNA transcription and splicing:
Characterizing the effect of microsatellite expansions on transcription and splicing will directly benefit therapeutic approaches for repeat expansion disorders. Proof-of-principle methods to locally disrupt the interactions of xtrRNA at repeat expansion loci, such as R-loops, have been demonstrated for FXS and FRDA using small molecules and nucleic acids.
For splicing-based therapeutics, blocking inclusion of repeat expansion-containing introns, such as with splice-modulating antisense oligonucleotides or small RNAs, could prove to be useful for disorders like FRDA and C9FTD/ALS.
With the emergence of gene editing technologies, the direct removal of repeat expansions from the genome may also be possible. Removal of genomic repeat expansions could eliminate the possibility of xtrRNA expression or reverse repressive epigenetic states.While potential CRISPR-based therapeutics are exciting, precautions must be taken to address potential pitfalls and challenges like off-target effects, delivery, and cell-type specific mechanisms of DNA damage repair

A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA)n Repeats Associated with Friedreich’s Ataxia

Ryan J. McGinty, Franco Puleo, Anna Y. Aksenova, Julia A. Hisey, Alexander A. Shishkin, Erika L. Pearson, Eric T. Wang, David E. Housman, Claire Moore, Sergei M. Mirkin, Cell Reports, Volume 20, Issue 10, 5 September 2017, Pages 2490-2500, ISSN 2211-1247, doi:10.1016/j.celrep.2017.08.051

Engineered Axonal Tracts as “Living Electrodes” for Synaptic-Based Modulation of Neural Circuitry

M. D. Serruya, J. P. Harris, D. O. Adewole, L. A. Struzyna, J. C. Burrell, A. D. Nemes, D. Petrov, R. H. Kraft, H. I. Chen, J. A. Wolf, D. K. Cullen, Adv. Funct. Mater. 2017, doi:10.1002/adfm.201701183

Brain–computer interface and neuromodulation strategies relying on penetrating non-organic electrodes/optrodes are limited by an inflammatory foreign body response that ultimately diminishes performance. A novel “biohybrid” strategy is advanced, whereby living neurons, biomaterials, and microelectrode/optical technology are used together to provide a biologically-based vehicle to probe and modulate nervous-system activity. Microtissue engineering techniques are employed to create axon-based “living electrodes”, which are columnar microstructures comprised of neuronal population(s) projecting long axonal tracts within the lumen of a hydrogel designed to chaperone delivery into the brain.

Friedrich’s ataxia: Patients develop severe motor impairments in the absence of pro­prioceptive and epicritic signals from the periphery. Living electrodes could provide an articial sensory arc: by tapping into signals from periphery (such as strain gauges, accelero­meters and gyroscopes worn at joints in all four limbs, or from implanted cuff recordings of peripheral nerves), living electrodes implanted into primary sensory cortices could pro­vide sensory feedback and allow improved voluntary move­ ment and functional independence. Grown with glutamatergic neurons, these living electrodes could be implanted to termi­nate in layer IV of the post­central gyrus; because living elec­trodes are themselves quite small, multiple constructs could be implanted corresponding to different joints (e.g., gyros from the left knee driving a living electrode implanted in the right medial sensory cortex, left elbow and shoulder to right lateral sensory cortex, and viceversa for the right extremities and left hemisphere).

Biogenesis and functions of mammalian iron-sulfur proteins in the regulation of iron homeostasis and pivotal metabolic pathways.

Tracey A. Rouault and Nunziata Maio; The Journal of Biological Chemistry 292, 12744-12753. doi: 10.1074/jbc.R117.789537

Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins.

Peptide SS-31 upregulates frataxin expression and improves the quality of mitochondria: implications in the treatment of Friedreich ataxia

Hongting Zhao, Huihui Li, Shuangying Hao, Jiping Chen, Jing Wu, Chuanhui Song, Meng Zhang, Tong Qiao & Kuanyu Li; Scientific Reports 7, Article number: 9840 (2017) doi:10.1038/s41598-017-10320-2

We demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients. Interestingly, SS-31 treatment translationally upregulated the protein level of frataxin in a dose-dependent manner. Furthermore, SS-31 treatment increased the enzymatic activities of the iron-sulphur enzymes, including aconitase and complex II and III of the respiratory chain. Further evaluation of the quality of mitochondria showed that mitochondrial membrane potential, ATP content, NAD+/NADH, and the morphology of mitochondria all improved. Our results suggest that SS-31 might potentially be a new drug for the early treatment of Friedreich ataxia.
In summary, SS-31 treatment improves the morphology and function of mitochondria in the FRDA patient-derived cells by upregulating the expression of FXN at the translational level and reducing oxidative stress. In addition, SS-31 treatment significantly enhances the ability of patient-derived cells to withstand challenges from exogenous oxidative stress. The mechanism of the translational upregulation in FXN expression by mitochondrion-targeted SS-31 needs to be further addressed. However, improvement in the quality of mitochondria in FRDA patient–derived cells by SS-31 treatment appears promising. It is reasonable to suggest that SS-31 might potentially be a new drug for the early treatment of FRDA.

Overexpression of Drosophila frataxin triggers cell death in an iron-dependent manner

Oliver Edenharter, Janik Clement, Stephan Schneuwly & Juan A. Navarro, Journal of Neurogenetics Vol. 0 , Iss. 0,0; doi:10.1080/01677063.2017.1363200

In this work, we have increased frataxin expression in neurons to elucidate specific roles that frataxin might play in these tissues. Using molecular, biochemical, histological and behavioral methods, we report that frataxin overexpression is sufficient to increase oxidative phosphorylation, modify mitochondrial morphology, alter iron homeostasis and trigger oxidative stress-dependent cell death. Interestingly, genetic manipulation of mitochondrial iron metabolism by silencing mitoferrin successfully improves cell survival under oxidative-attack conditions, although enhancing antioxidant defenses or mitochondrial fusion failed to ameliorate frataxin overexpression phenotypes. This result suggests that cell degeneration is directly related to enhanced incorporation of iron into the mitochondria. Drosophila frataxin overexpression might also provide an alternative approach to identify processes that are important in FRDA such as changes in mitochondrial morphology and oxidative stress induced cell death.

Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

Jeffrey R. Liddell, Antioxidants 2017, 6(3), 65; doi:10.3390/antiox6030065

This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs.

Jupiter Orphan Therapeutics Receives Orphan Drug Designation for its Trans-Resveratrol Product JOTROL for Treatment of Friedreich's Ataxia

JUPITER, Fla., Aug. 22, 2017 /PRNewswire/ -- Jupiter Orphan Therapeutics, Inc. ("JOT"), Jupiter, FL, today announced that it has received notification from the US Food and Drug Administration (FDA) that its Orphan Drug Designation request for trans-Resveratrol has been granted.

"Orphan Drug Designation serves as an important milestone for JOT as it positions our JOTROL™ product as a potential treatment for FA. We are hopeful that JOTROL™ can ultimately provide a meaningful treatment for FA patients around the world based on the earlier Phase II trial, utilizing resveratrol, conducted by our partner Murdoch Children's Research Institute, Melbourne, Australia ("MCRI"). That trial was an open label trial and generated very encouraging results, where 4 out of 5 very important endpoints were met. We, JOT together with MCRI, expect to repeat these results through a larger placebo controlled study utilizing JOTROL™ to avoid the Gastro Intestinal (GI) tolerability issues.

Assessment of glutathione/glutathione disulphide ratio and S-glutathionylated proteins in human blood, solid tissues, and cultured cells

Daniela Giustarini, Graziano Colombo, Maria Lisa Garavaglia, Emanuela Astori, Nicola Marcello Portinaro, Francesco Reggiani, Salvatore Badalamenti, Anna Maria Aloisi, Annalisa Santucci, Ranieri Rossi, Aldo Milzani, Isabella Dalle-Donne, Free Radical Biology and Medicine, Available online 12 August 2017, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2017.08.008.

Glutathione (GSH) is the major non-protein thiol in humans and other mammals, which is present in millimolar concentrations within cells, but at much lower concentrations in the blood plasma. GSH and GSH-related enzymes act both to prevent oxidative damage and to detoxify electrophiles. Under oxidative stress, two GSH molecules become linked by a disulphide bridge to form glutathione disulphide (GSSG). Therefore, assessment of the GSH/GSSG ratio may provide an estimation of cellular redox metabolism. Current evidence resulting from studies in human blood, solid tissues, and cultured cells suggests that GSH also plays a prominent role in protein redox regulation via S-glutathionylation.

By immunohistochemistry with anti-GSH antibody, PSSG were also detected in Friedreich's ataxia, an autosomal recessive disorder caused by mutations in the gene encoding frataxin. In particular, in the cervical sections of spinal cord derived from autopsies of individuals with Friedreich's ataxia, immunostaining with anti-GSH antibodies was significantly stronger than in control sections, suggesting a significant increase in PSSG amount in all grey matter neurons, particularly in motor neurons of the anterior horns, as well as in the axonal spinal tracts (mostly in posterior white columns, spinocerebellar and corticospinal tracts). These findings suggest the occurrence of oxidative stress in the spinal cord of patients with Friedreich's ataxia as a consequence of reduced frataxin expression.

European Reference networks for rare diseases: what is the conceptual framework?

Véronique Héon-Klin, Orphanet Journal of Rare Diseases 201712:137 doi:10.1186/s13023-017-0676-3

In February 2017, 24 European Reference Networks (ERNs) were established in a European legal framework, of which 23 are dedicated to rare or low prevalence complex diseases or conditions. More than 300 hospitals and 900 highly specialised teams are participating in the approved ERN.

The ERNs are an opportunity to explore these changes and turn them into assets for patients with unmet needs. If we succeed in promote knowledge exchange in such a way that patients will only be treated in duly justified cases in the “other” MS, then “the European social model in health” can be preserved under the current European treaties.

Advances in Neurological Therapeutics for Friedreich Ataxia and Machado-Joseph Disease

Yabe I, Sasaki H.; Brain Nerve. 2017 Aug;69(8):913-924. doi: 10.11477/mf.1416200842.
[Article in Japanese]
We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined.

Cerebral Abnormalities in Friedreich Ataxia: A Review

Louisa P. Selvadurai, Ian H. Harding, Louise A. Corben, Nellie Georgiou-Karistianis, Neuroscience & Biobehavioral Reviews, Available online 18 August 2017, ISSN 0149-7634, doi:10.1016/j.neubiorev.2017.08.006.

However, cerebral abnormalities in FRDA are being increasingly documented via multiple neuroimaging techniques. Understanding the nature and implications of cerebral abnormalities in FRDA provides more comprehensive knowledge of nervous system involvement in this disorder and increases the prospects of identifying effective treatment targets. We review the cerebellar and the cerebral involvement with a focus on the emerging in vivo human neuroimaging findings suggesting wide-spread cerebral involvement, including aberrant cerebellar-cerebral connectivity. We synthesise the findings by proposing potential mechanisms that may drive these effects. Finally, we identify future research directions which, we argue, will lead to a better understanding of the extent and potential mechanisms of cerebral aberrations in FRDA.