Data Readout from Potentially Pivotal Phase 2/3 INAD Trial Expected 1H ‘01; Phase 2 ALS and Pivotal Phase 2/3 Friedreich’s Ataxia Trial Readouts Expected by Year-End

LOS ALTOS, Calif., Feb. 11, 2021 (GLOBE NEWSWIRE)​. RT001 Clinical Program Highlights: Friedreich’s Ataxia (FA) – Enrollment was completed in the ongoing pivotal Phase 2/3 trial of RT001 in FA in late 2020. Data from this trial is expected to read out by the end of 2021. Proof-of-concept for RT001 in FA was demonstrated in the company’s previously completed Phase 1/2 placebo-controlled trial. FA is a rare, debilitating, life-shortening pediatric neurodegenerative disease. Like INAD, FA qualifies for RPD designation and a RPD voucher from FDA.

Future Prospects of Gene Therapy for Friedreich’s Ataxia

Ocana-Santero, G.; Díaz-Nido, J.; Herranz-Martín, S.; Int. J. Mol. Sci. 2021, 22, 1815. doi:10.3390/ijms22041815 

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.

Sheffield university team awarded £1.6m for drug research​​​​​​​ on motor neurone disease

Sheffield Telegraph; It will support their partnership with Aclipse Therapeutics to advance the translational development of M102 - a drug candidate for the treatment of motor neurone disease (MND). Aclipse says M102 may also have potential to treat Friedreich’s ataxia, Huntington's disease and Parkinson's disease.

Gauging Gait Disorders with a Method Inspired by Motor Control Theories: A Pilot Study in Friedreich’s Ataxia

Gouelle, A.; Norman, S.; Sharot, B.; Salabarria, S.; Subramony, S.; Corti, M. Gauging; Sensors 2021, 21, 1144. doi:10.3390/s21041144 

 Organization Scores demonstrated a longitudinal deterioration in the gait characteristics from independent ambulators to those who ambulated with a rollator. Variability Scores mostly reflected dynamic instability, which became greater as the requirement of an ambulation aid or the switch from a cane to a rollator was imminent. The global value given by the Global Ambulation Score, which takes into consideration both the Organization Score, the Variability Score, and the level of assistive device, demonstrated a logarithmic relationship with the SARA-GS. Overall, these results highlight that both components introduced should be analyzed concurrently and suggest that the Global Ambulation Score may be a valuable outcome measure for longitudinal disease progression.

Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich's ataxia fibroblasts

Floriane Petit, Anthony Drecourt, Michaël Dussiot, Coralie Zangarelli, Olivier Hermine, Arnold Munnich, Agnes Rotig; Blood blood.2020006987. doi:10.1182/blood.2020006987 

 Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in the cytosol and mitochondria. We observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed transferrin recycling, ascribing this to impaired TfR1 palmitoylation. Frataxin deficiency is shown to reduce coenzyme A (CoA) availability for TfR1 palmitoylation. Finally, we demonstrate that artesunate, CoA, and dichloroacetate improve TfR1 palmitoylation and decrease iron overload, paving the road for evidence-based therapeutic strategies at the actionable level of TfR1 palmitoylation in FRDA.

Therapeutic roles of natural remedies in combating hereditary ataxia: A systematic review

Michael Weng Lok Phang, Sze Yuen Lew, Ivy Chung, William Kiong-Seng Lim, Lee Wei Lim & Kah Hui Wong; Chin Med 16, 15 (2021). https://doi.org/10.1186/s13020-020-00414-x

Ten pre-clinical and two clinical studies were eligible for inclusion in this systematic review. We identified the therapeutic roles of medicinal plants Brassica napus, Gardenia jasminoides, Gastrodia elata, Ginkgo biloba, Glycyrrhiza inflata, Paeonia lactiflora, Pueraria lobata and Rehmannia glutinosa; herbal formulations Shaoyao Gancao Tang and Zhengan Xifeng Tang; and medicinal mushroom Hericium erinaceus in the treatment of HA. In this review, we evaluated the mode of actions contributing to their therapeutic effects, including activation of the ubiquitin–proteasome system, activation of antioxidant pathways, maintenance of intracellular calcium homeostasis and regulation of chaperones. We also briefly highlighted the integral cellular signalling pathways responsible for orchestrating the mode of actions.

Replication-independent instability of Friedreich's ataxia GAA repeats during chronological aging

Neil AJ, Hisey JA, Quasem I, McGinty RJ, Hitczenko M, Khristich AN, Mirkin SM.; Proc Natl Acad Sci U S A. 2021 Feb 2;118(5):e2013080118. doi: 10.1073/pnas.2013080118.

Somatic instability is commonly observed in terminally differentiated, postmitotic cells, such as neurons. To unravel the mechanisms of repeat instability in nondividing cells, we created an experimental system to analyze the mutability of Friedreich's ataxia (GAA)n repeats during chronological aging of quiescent Saccharomyces cerevisiae Unexpectedly, we found that the predominant repeat-mediated mutation in nondividing cells is large-scale deletions encompassing parts, or the entirety, of the repeat and adjacent regions. These deletions are caused by breakage at the repeat mediated by mismatch repair (MMR) complexes MutSβ and MutLα and DNA endonuclease Rad1, followed by end-resection by Exo1 and repair of the resulting double-strand breaks (DSBs) via nonhomologous end joining. We also observed repeat-mediated gene conversions as a result of DSB repair via ectopic homologous recombination during chronological aging. Repeat expansions accrue during chronological aging as well-particularly in the absence of MMR-induced DSBs. These expansions depend on the processivity of DNA polymerase δ while being counteracted by Exo1 and MutSβ, implicating nick repair. Altogether, these findings show that the mechanisms and types of (GAA)n repeat instability differ dramatically between dividing and nondividing cells, suggesting that distinct repeat-mediated mutations in terminally differentiated somatic cells might influence Friedreich's ataxia pathogenesis.

Ectopic Burden Via Holter Monitors in Friedreich’s Ataxia,

Erika Mejia, Abigail Lynch, Patrick Hearle, Oluwatimilehin Okunowo, Heather Griffis, Maully Shah, David Lynch, Kimberly Y. Lin; Pediatric Neurology, 2021, doi:10.1016/j.pediatrneurol.2021.01.004. 

Patients with longer disease duration had higher rates of SVE. Heart rhythm monitoring may be considered for risk stratification, however longitudinal analysis is needed.

AVXS-401, by Novartis Gene Therapies

25/01/2021. AVXS-401 is a gene therapy developed by Novartis Gene Therapies (AveXis, now is part of Novartis). It uses the AAV9 adeno-associated virus (AAV) vector to deliver a functional copy of the FXN gene to restore the production of frataxin in tissues that are severely affected by FA. Early toxicity studies conducted in healthy mice showed that AVXS-401 has good safety and tolerability. Efficacy studies have shown that in a FA mouse model lacking frataxin in the central nervous system, a single intracerebroventricular (ICV) injection of low-dose AVXS-401 can improve behavior and promote glial cell proliferation. In a mouse model lacking frataxin in the heart, AVXS-401 can restore heart function, prolong the median survival by more than 3 times, and prevent the onset of cardiovascular disease. When the therapeutic dose is increased proportionally and administered in non-human primates, AVXS-401 can achieve sustained expression of frataxin in the central nervous system and heart, and the effect is still obvious after 6 months of treatment.

Novartis Gene Therapies gets FDA Orphan Drug Designation in Friedreich's Ataxia

01/21/2021. Novartis Gene Therapies gets FDA Orphan Drug Designation in Friedreich's Ataxia, Novartis Gene Therapies announced that the U.S. Food and Drug Administration has granted Orphan Drug Designation for its "Adeno-associated virus isoform 9 gene vector construct expressing the human Frataxin gene" for the treatment of Friedreich's Ataxia.

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Generic Name:	Adeno-associated virus isoform 9 gene vector construct expressing the human Frataxin gene
Date Designated:	01/21/2021
Orphan Designation:	Treatment of Friedreich`s Ataxia.
Orphan Designation Status:	Designated
FDA Orphan Approval Status:	Not FDA Approved for Orphan Indication
Sponsor:	Novartis Gene Therapies 2275 Half Day Road, Suite 300 Bannockburn, Illinois 60015 United States The sponsor address listed is the last reported by the sponsor to OOPD.

*Exclusivity Protected Indications are shown for approvals from Jan. 1, 2013, to the present.