'Editorial: The Mechanistic Investigation and Emerging Therapies for Friedreich's Ataxia'

Yina Dong, Vijayendran Chandran, Elisabetta Soragni, David R Lynch, Front. Pharmacol. Sec. Neuropharmacology Volume 16 - 2025 doi:10.3389/fphar.2025.1560808

By integrating mechanistic insights with novel therapeutic approaches and outcome measures, this collection paves the way for more comprehensive and effective interventions for FRDA patients.

Larimar Therapeutics Announces Dosing of Adolescents in Nomlabofusp Pediatric Pharmacokinetic Run-In Study for Patients with Friedreich’s Ataxia

BALA CYNWYD, Pa., Jan. 23, 2025 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), today announced that dosing of adolescents 12-17 years old has started in the Company’s pediatric PK run-in study for patients with Friedreich’s ataxia (FA). 

 “Dosing adolescents is the first step in evaluating the safety and PK of nomlabofusp in pediatric patients with FA. We continue to enroll adolescents in our first cohort. This cohort will be followed by a second cohort of children 2-11 years old. We expect to transition both the adolescents and children into the ongoing OLE study after assessing safety and exposure data from each successive cohort,” said Dr. Rusty Clayton, Chief Medical Officer of Larimar. “We look forward to reporting long-term 50 mg data in adults from our OLE study, as well as available data from adolescents completing the pediatric PK run-in study, in mid- 2025.”

Hypoxia as a medicine

Robert S. Rogers, Vamsi K. Mootha. Hypoxia as a medicine. Science Translational Medicine 22 Jan 2025 Vol 17, Issue 782 DOI: 10.1126/scitranslmed.adr4049

Oxygen is essential for human life, yet a growing body of preclinical research is demonstrating that chronic continuous hypoxia can be beneficial in models of mitochondrial disease, autoimmunity, ischemia, and aging. This research is revealing exciting new and unexpected facets of oxygen biology, but translating these findings to patients poses major challenges, because hypoxia can be dangerous.

Solid Biosciences Receives FDA Fast Track Designation for SGT-212 Dual Route of Administration Gene Therapy for Friedreich’s Ataxia

CHARLESTOWN, Mass., Jan. 21, 2025 (GLOBE NEWSWIRE) -- Solid Biosciences Inc. today announced that it has received Fast Track designation from the U.S. Food and Drug Administration (FDA) for SGT-212, the Company’s, AAV-based gene therapy candidate for the treatment of Friedreich’s ataxia (FA). SGT-212 will deliver the full-length frataxin gene via dual routes of administration incorporating intradentate nucleus (IDN) and intravenous (IV) infusions, designed to promote restoration of therapeutic levels of the frataxin protein to address neurologic, cardiac and systemic clinical manifestations of FA.

Friedreich ataxia: what can we learn from non-GAA repeat mutations?

Lynch DR, Shen M, Wilson RB. Friedreich ataxia: what can we learn from non-GAA repeat mutations? Neurodegener Dis Manag. 2025 Jan 15:1-10. doi: 10.1080/17582024.2025.2452147. Epub ahead of print. PMID: 39810561. 

 Compound heterozygote patients with one expanded GAA allele and a non-GAA repeat mutation can have subtle differences in phenotype from typical FRDA, including, in patients with selected missense mutations, both more severe features and less severe features in the same patient. In this review, we propose explanations for such phenotypes based on the potential for activities of frataxin other than enhancement of iron-sulfur cluster synthesis, as well as crucial future experiments for fully understanding the role of frataxin in cells.

Altered Intracerebellar Functional Connectivity in Friedreich's Ataxia: A Graph-Theory Functional MRI Study

Tranfa M, Costabile T, Pontillo G, Scaravilli A, Pane C, Brunetti A, Saccà F, Cocozza S. Altered Intracerebellar Functional Connectivity in Friedreich's Ataxia: A Graph-Theory Functional MRI Study. Cerebellum. 2025 Jan 14;24(2):30. doi: 10.1007/s12311-025-01785-3. PMID: 39808241; PMCID: PMC11732920. 

Graph analysis revealed regional intra-cerebellar FC changes in FRDA, marked by reduced functional centrality in cerebellar regions of the vermis and responsible for executive functions. These changes correlated with cognitive alterations, highlighting the role of the cerebellar cortex in the cognitive impairment observed in FRDA. In conclusion, our observations confirm that the cerebellum is involved in the pathophysiology of FRDA not only from a structural, but also from a functional standpoint, and suggests that integrating information from different parcellations could provide complementary knowledge and help us in decoding the exact relationship between FC alterations and cognitive changes in FRDA.

Life and death of Yfh1: how cool is cold denaturation

Temussi PA, Martin SR, Pastore A. Life and death of Yfh1: how cool is cold denaturation. Q Rev Biophys. 2025 Jan 13;58:e2. doi: 10.1017/S0033583524000180. PMID: 39801016. 

 The present review aims at recapitulating all the open questions that Yfh1 has helped to address, including understanding the differences and commonalities of the cold, heat and pressure unfolded states. This protein thus offers a unique tool for studying aspects of protein stability so far been considered difficult to assess and provides important guidelines that could allow the identification of other similar systems.

Longitudinal analysis of anthropometric measures over 5 years in patients with Friedreich ataxia in the EFACTS natural history study

Lischewski SA, Konrad K, Dogan I, Didszun C, Costa AS, Schawohl SA, Giunti P, Parkinson MH, Mariotti C, Nanetti L, Durr A, Ewenczyk C, Boesch S, Nachbauer W, Klopstock T, Stendel C, de Rivera Garrido FJR, Schöls L, Fleszar Z, Klockgether T, Grobe-Einsler M, Giordano I, Rai M, Pandolfo M, Schulz JB, Reetz K; EFACTS study group. Longitudinal analysis of anthropometric measures over 5 years in patients with Friedreich ataxia in the EFACTS natural history study. Eur J Neurol. 2025 Jan;32(1):e70011. doi: 10.1111/ene.70011. PMID: 39797559; PMCID: PMC11724196. 

Significant anthropometric abnormalities were identified, with underweight and short stature prevalent in children and overweight in adults. These findings highlight the need for regular nutritional monitoring and interventions to manage underweight in children and promote healthy weight in adults.

Effects of physiotherapy on degenerative cerebellar ataxia: a systematic review and meta-analysis

Matsugi A, Bando K, Kondo Y, Kikuchi Y, Miyata K, Hiramatsu Y, Yamanaka Y, Tanaka H, Okuda Y, Haruyama K and Yamasaki Y (2025) Effects of physiotherapy on degenerative cerebellar ataxia: a systematic review and meta-analysis. Front. Neurol. 15:1491142. doi: 10.3389/fneur.2024.1491142

Physical therapy, especially multi-aspect physical therapy such as muscle strengthening, coordination training, gait training, and ADL training, may reduce DCA symptoms. Further, balance and aerobic training can be added to the program. However, the estimated effect size may change in future studies because of the serious RoB, very low certainty of evidence, and high heterogeneity with SARA as the primary outcome. High-quality RCTs are required to establish evidence for the effectiveness of physical therapy in patients with DCA.

Poincaré plot analysis of ECG uncovers beneficial effects of omaveloxolone in a mouse model of Friedreich’s ataxia

Poincaré plot analysis of ECG uncovers beneficial effects of omaveloxolone in a mouse model of Friedreich’s ataxia, Figueroa, Francisco et al., Heart Rhythm, Volume 0, Issue 0. DOI: 10.1016/j.hrthm.2024.12.041

Our study revealed significant electrical propagation disturbances and sexual dimorphism in FXN-cKO mice with severe cardiomyopathy. Poincaré plots identified irregularities in heart rhythm and ANS dysfunction. OMAV improved heart function by stabilizing early repolarization and reducing disparate arrhythmias. This work stresses sex-specific ECG interpretations and alternative mathematical approaches for drug testing in FA models.

Capsida Announces AbbVie Opt-in for First Genetic Medicine Program from Neurodegenerative Disease Collaboration

THOUSAND OAKS, Calif., Jan. 7, 2025 /PRNewswire/ -- Capsida Biotherapeutics ("Capsida") today announced that AbbVie has exercised an option for the first neurodegenerative disease program under their ongoing collaboration. Capsida will receive a $40 million license payment and is eligible for additional milestones and royalties.

Capsida's wholly owned pipeline includes a potential first-in-class treatment for STXBP1 developmental and epileptic encephalopathy, best-in-class treatment for Parkinson's disease associated with GBA mutations, and best-in-class therapy for Friedreich's ataxia. In addition to its wholly owned programs, the Company has validating partnerships with AbbVie, Lilly, and CRISPR Therapeutics.

Solid Biosciences Announces FDA IND Clearance for First-In-Industry Dual Route of Administration Gene Therapy to Treat Both Neurologic and Cardiac Manifestations of Friedreich’s Ataxia

CHARLESTOWN, Mass., Jan. 07, 2025 (GLOBE NEWSWIRE) -- Solid Biosciences Inc. today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for SGT-212 for the treatment of Friedreich’s ataxia (FA). SGT-212 is the Company’s novel, AAV-based FA gene therapy candidate designed to deliver full-length frataxin via systemic intravenous (IV) infusion as well as direct intradentate nuclei (IDN) infusion into the cerebellum. SGT-212 is designed to treat the neurologic and systemic clinical manifestations of FA to address the full spectrum of disease progression. 

In the second half of 2025, the Company expects to initiate a first-in-human, open-label, dose-finding Phase 1b clinical trial of SGT-212. The study will enroll non-ambulatory and ambulatory adult patients living with FA across up to three cohorts and will evaluate the safety and tolerability of contemporaneous systemic and bilateral IDN administration of SGT-212. Participants in the trial will be followed out to five years after receiving SGT-212.

Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease

Hisey JA, Masnovo C, Mirkin SM. Triplex H-DNA structure: the long and winding road from the discovery to its role in human disease. NAR Mol Med. 2024 Dec 5;1(4):ugae024. doi: 10.1093/narmme/ugae024. PMID: 39723156; PMCID: PMC11667243. 

H-DNA-forming repeats have been implicated in four REDs: Friedreich's ataxia, GAA-FGF14-related ataxia, X-linked Dystonia Parkinsonism, and cerebellar ataxia, neuropathy and vestibular areflexia syndrome. In this review, we summarize H-DNA's discovery and characterization, evidence for its existence and function in vivo, and the field's current knowledge on its role in physiology and pathology.

Harshly Oxidized Activated Charcoal Enhances Protein Persulfidation with Implications for Neurodegeneration as Exemplified by Friedreich's Ataxia

Vo ATT, Khan U, Liopo AV, Mouli K, Olson KR, McHugh EA, Tour JM, Pooparayil Manoj M, Derry PJ, Kent TA. Harshly Oxidized Activated Charcoal Enhances Protein Persulfidation with Implications for Neurodegeneration as Exemplified by Friedreich's Ataxia. Nanomaterials (Basel). 2024 Dec 13;14(24):2007. doi: 10.3390/nano14242007. PMID: 39728543. 

We demonstrate that pleozymes increased overall protein persulfidation in cells from apparently healthy individuals and from individuals with the mitochondrial protein mutation responsible for Friedreich's ataxia. We further find that pleozymes specifically enhanced Keap1 persulfidation, with subsequent increased accumulation of Nrf2 and Nrf2's antioxidant targets.