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

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

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

Gene therapy for neurological disorders: progress and prospects

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

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

Longitudinal analysis of contrast acuity in Friedreich ataxia

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

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

Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

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

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

Novoheart, Pfizer develop 3-D model of Friedreich ataxia

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

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

ClinicalTrials.gov Identifier: NCT03607058

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

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

Public offering nets $203mm for Reata

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

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

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

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

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

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

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

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

SOURCE Monash University

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

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