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.