Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia

Daniel M. DuBreuil, Michael Fleming, Yashvi Parikh, Mikaela Woo, Jie Bu, Swathi Ayloo, Ingeborg M. Langohr, Dinesh S. Bangari, Christian Mueller, Shyam Ramachandran, Development of a secretable frataxin for enhanced efficacy in treating Friedreich’s Ataxia, Molecular Therapy Advances, 2025, 201661, ISSN 3117-387X, doi:10.1016/j.omta.2025.201661. 

No disease-modifying therapies are approved for FA, and current gene therapy approaches fail to address the full disease, forcing patients to choose between cardiac protection or neurological benefit. Here, we present ‘Engineered Cross-Correction,’ in which the therapeutic protein is bioengineered for secretion, expanding the therapeutic footprint. We apply this approach to FA by engineering a secretable frataxin and delivering it via a single intra-cerebrospinal fluid (CSF) injection of an adeno-associated viral (AAV) vector equipped with a novel capsid and tissue-selective promoter. We achieved broad protein repletion across key target tissues—heart, dorsal root ganglia, and cerebellum—in mouse and non-human primate. In FA mouse models, we observed rescue of cardiac and neurological phenotypes, marking the first demonstration of dual correction with a single, minimally invasive administration. These benefits were achieved without widespread transduction, reducing vector burden and associated toxicity. Our findings establish a scalable platform that contrasts with intravenous BBB-penetrant gene delivery and offers a generalizable strategy for multi-system disorders. Beyond FA, this positions Engineered Cross-Correction as a new frontier for the next generation of gene therapies.

Using a discrete choice experiments to explore societal preferences for valuing new drugs for rare diseases

Vargas, C., Goodall, S., Street, D.J. et al. Using a discrete choice experiments to explore societal preferences for valuing new drugs for rare diseases. Orphanet J Rare Dis 20, 631 (2025). doi:10.1186/s13023-025-04141-0 

Results In general, respondents had a greater preference for drugs that increase survival, where there was greater confidence in the effectiveness of the new drug and which increased patients’ capacity to do their usual activities. Preferences were not homogenous, the latent class analysis identified three groups: Class 3 (58%) demonstrated a strong preference for improvements in survival; Class 2 (21%) showed a strong preference for confidence in the evidence; and Class 1 (21%) positively valued increased government expenditure. 

Conclusion These results are consistent with previous studies that used different methodologies in showing a preference for drugs with improved survival and quality of life. However, addressing a societal preference for greater confidence in the evidence - reducing evidential uncertainty - represents a methodological and policy challenge for the evaluation of drugs in rare diseases.

Progressive scoliosis in a pediatric patient with cerebellar ataxia: surgical challenges and literature review

Asunis E, Vitulli F, Nicotra R, Rubino A, Cicala D, Cinalli G, Colella G. Progressive scoliosis in a pediatric patient with cerebellar ataxia: surgical challenges and literature review. Childs Nerv Syst. 2025 Dec 15;41(1):418. doi: 10.1007/s00381-025-07091-x. PMID: 41396316. 

 Spinal fusion can be performed safely in pediatric SCA/FA patients when meticulous multidisciplinary planning, individualized neuromonitoring strategies, and aggressive postoperative rehabilitation are adopted. Early recognition of underlying ataxia is critical for risk stratification and the timing of intervention. Prospective, longitudinal studies are warranted to refine guidelines and optimize neurological and orthopedic results in this complex population.

Digital Gait Measures Discriminate People with Friedreich's Ataxia from Healthy Controls

Casey HL, Shah VV, Muzyka D, McNames J, El-Gohary M, Sowalsky K, Safarpour D, Carlson-Kuhta P, Schmahmann JD, Rosenthal LS, Perlman S, Rummey C, Horak FB, Gomez CM. Digital Gait Measures Discriminate People with Friedreich's Ataxia from Healthy Controls. Mov Disord Clin Pract. 2025 Dec 17. doi: 10.1002/mdc3.70465. Epub ahead of print. PMID: 41408995. 

Digital gait measures from wearable sensors were discriminative, reliable, and showed concurrent validity for evaluating ataxia severity during an instrumented walk test. These results suggest promising utility of digital gait outcomes for use in FRDA clinical trials.

Neuropathology of Friedreich ataxia and its links to metabolic pathways

Mercado-Ayón E, Lazaropoulos MP, Mercado-Ayón Y, Lynch DR. Neuropathology of Friedreich ataxia and its links to metabolic pathways. Neurodegener Dis Manag. 2025 Dec 25:1-12. doi: 10.1080/17582024.2025.2607957. Epub ahead of print. PMID: 41447358. 

This review highlights recent insights into the neuropathology of FRDA, emphasizing the detailed developmental timing of neuroanatomical changes. It also focuses on selective mitochondrial metabolic pathways, including fatty acid metabolism, ceramide synthesis, and ketogenesis, which may underlie neuron-specific vulnerability and serve as potential targets for pharmacological or dietary intervention. The possibility of non-traditional interventions based on metabolic features of FRDA offers hope for ameliorating the severity of FRDA.

Unrecognized high prevalence of expanded composite repeats in Friedreich ataxia

Devore MC, Lam C, Wiley G, Park CC, Lynch DR, Bidichandani SI. Unrecognized high prevalence of expanded composite repeats in Friedreich ataxia. Hum Mol Genet. 2025 Dec 23:ddaf190. doi: 10.1093/hmg/ddaf190. Epub ahead of print. PMID: 41432640. 

In a prospective series of 112 unrelated patients, we found that approximately 20% of people with Friedreich ataxia have at least one such expanded composite allele. Other minor sequence interruptions in the expanded GAA repeat were detected in a further 10% of patients. Most expanded composite alleles revealed by longread genome sequencing are not detectable by standard PCR-based testing, and have therefore remained hidden despite their relatively high prevalence. This results in erroneous genotyping of patients and heterozygous carriers.

(Italy). The first treatment (Skyclarys) for Friedreich's ataxia will be reimbursed by the National Health Service

At its meeting on 15 December, the AIFA Board of Directors gave the green light to the reimbursement of Skyclarys (omaveloxolone), an orphan drug for the treatment of Friedreich's ataxia.

Skyclarys, the first medicine proven to slow the progression of the disease, was authorised by the European Medicines Agency (EMA) in February 2024 and included by AIFA in July 2024 in the list of medicines distributed under Law No. 648/1996, an early access programme that allows free dispensing to eligible patients, with the cost entirely covered by the National Health Service. Now, following negotiations with the marketing authorisation holder, the medicine will be available for reimbursement for the treatment of patients aged 16 years and older, upon prescription by centres for the treatment of rare diseases.

Respiratory Function in Friedreich's Ataxia

Viana CF, Jaques CS, Bezerra MLE, Barsottini OGP, Pedroso JL. Respiratory Function in Friedreich's Ataxia. Mov Disord. 2025 Dec 19. doi: 10.1002/mds.70162. Epub ahead of print. PMID: 41416841. 

FA patients exhibited significantly reduced forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), alongside decreased maximal respiratory pressures (P < 0.01). A restrictive ventilatory pattern predominated. Peripheral oxygen saturation was lower in the FA group (P < 0.01). 

Respiratory impairment appears mostly subclinical, suggesting that FA patients may be vulnerable to pulmonary infections and ventilatory failure. This dysfunction may reflect both neuromuscular weakness and impaired respiratory coordination. Early and regular respiratory assessment, together with preventive and rehabilitative strategies integrated into multidisciplinary care, may improve quality of life and potentially prolong survival in individuals with FA.

Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway

Campbell, T., Slone, J., Vu, J. et al. Ferroptosis is a novel pathogenic mechanism of FDXR-related disease via disruption of the NRF2 pathway. Cell Death Discov. 11, 563 (2025). doi:10.1038/s41420-025-02840-y  

Our results suggest that ferroptosis is a novel underlying mechanism of FDXR-related disease and that activation of NRF2 could be an immediate, viable treatment option for individuals with FDXR-related disease and other conditions involving aberrant iron metabolism.

Targeting Friedreich Ataxia: A Sustainable Path to Safer and Smarter Therapeutics Through Integrated Docking and Toxicology

H. B. Attel, R. P, A. K, B. S, Shivandappa and S. Manokaran, "Targeting Friedreich Ataxia: A Sustainable Path to Safer and Smarter Therapeutics Through Integrated Docking and Toxicology," 2024 8th International Conference on Computational System and Information Technology for Sustainable Solutions (CSITSS), Bengaluru, India, 2024, pp. 1-4, doi: 10.1109/CSITSS64042.2024.10816941. 

 Our study aims to develop novel therapeutic candidates by leveraging computational protein-ligand docking through the Galaxy EU platform, targeting frataxin deficiencies. High-throughput docking and toxicology studies have identified several promising compounds with potential therapeutic efficacy, offering hope for more effective and sustainable treatments for FA.

The NCPE recommends that omaveloxolone not be considered for reimbursement

NCPE assessment completed, 16/12/2025. The National Centre for Pharmacoeconomics (NCPE) is a team of experts who look at the health benefits and costs of medicines. The HSE asks us to advise on whether or not a new medicine is good value for money. We give unbiased advice to help the HSE provide the most effective, safe and cost-effective (value for money) treatments for patients. 

After reviewing the data presented by the pharmaceutical company, we recommend that the HSE consider not providing omaveloxolone. This is because we are unsure based on the available clinical evidence that omaveloxolone leads to meaningful improvements in Friedreich’s ataxia symptoms. The current price of the medicine is too high, and there is no price at which omaveloxolone can be cost effective. We believe that the medicine is very poor value for money.

Cross-regulation of [2Fe–2S] cluster synthesis by ferredoxin-2 and frataxin

Want, K., Gorny, H., Turki, E. et al. Cross-regulation of [2Fe–2S] cluster synthesis by ferredoxin-2 and frataxin. Nature (2025). doi: 10.1038/s41586-025-09822-1 

 Using an in-vitro-reconstituted human system, we show that any deviation from a close-to-equal amount of FXN and FDX2 downregulates Fe–S cluster synthesis. Structure–function investigation reveals that this is due to competition between FXN and FDX2 and their similar affinities for the same binding site on the NFS1–ISCU2 complex, with higher levels of FXN impairing the persulfide reductase activity of FDX2 and higher levels of FDX2 slowing the FXN-accelerated transfer of persulfide to ISCU2. We also find that FDX2 directly hinders persulfide generation and transfer to ISCU2 by interacting with the persulfide-carrying mobile loop of NFS1. We further show that knocking down the expression of FDX2 increases fly lifespan in a Drosophila model of Friedreich’s ataxia. Together, this work highlights a direct regulation of Fe–S cluster biosynthesis through antagonistic binding of FXN and FDX2, and suggests that decreasing FDX2 in the context of FXN deficiency in Friedreich’s ataxia might constitute a novel therapeutic axis.

Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency

Meisel, J.D., Joshi, P.R., Spelbring, A.N. et al. Mutations in mitochondrial ferredoxin FDX2 suppress frataxin deficiency. Nature (2025). doi:10.1038/s41586-025-09821-2 

We show that lowering levels of wild-type FDX2 through loss of one gene copy can ameliorate the growth of frataxin mutant C. elegans or the ataxia phenotype of a mouse model of Friedreich’s ataxia under normoxic conditions. These genetic and biochemical studies indicate that restoring the stoichiometric balance of frataxin and FDX2 through partial knockdown of FDX2 may be a potential therapy for Friedreich’s ataxia.

Eli Lilly (LLY) Completes Acquisition of Adverum Biotechnologies

Eli Lilly (LLY) Completes Acquisition of Adverum Biotechnologies. GuruFocus News 12/09/2025. 

This acquisition enhances Eli Lilly's portfolio, which also includes promising candidates for retinitis pigmentosa and Friedreich's ataxia.

Solid Biosciences Receives FDA Rare Pediatric Disease Designation for SGT-212 Dual Route of Administration Gene Therapy for Friedreich’s Ataxia

CHARLESTOWN, Mass., Dec. 01, 2025 (GLOBE NEWSWIRE) -- Solid Biosciences Inc. today announced that it received Rare Pediatric Disease designation from the U.S. Food and Drug Administration (FDA) for SGT-212, the Company’s investigational gene therapy for Friedreich’s ataxia (FA). SGT-212 will deliver the full-length frataxin gene via dual routes of administration, utilizing both direct intradentate nucleus (IDN) and intravenous (IV) infusions, and was designed to promote restoration of therapeutic levels of the frataxin protein to address neurologic, cardiac and systemic clinical manifestations of FA.

Together with the Fast Track designation granted earlier this year, it recognizes our dual-route clinical approach for FALCON, our first-in-human trial, which is now screening participants, as an important first step in meeting an unmet need for FA. These designations are designed to help accelerate time to market and enhance engagement with the FDA. We look forward to continued collaboration with regulators to bring this therapy to patients as quickly as possible.

Enhancing the Objective Assessment of Friedreich Ataxia Severity: A Multiview IMU-Based Approach

Ranaweera K, Nguyen BA, Pathirana PN, Milne SC, Horne M, Delatycki MB, Corben LA. Enhancing the Objective Assessment of Friedreich Ataxia Severity: A Multiview IMU-Based Approach. Annu Int Conf IEEE Eng Med Biol Soc. 2025 Jul;2025:1-6. doi: 10.1109/EMBC58623.2025.11253596. PMID: 41335798. 

These findings indicate that multiview IMU-based systems can provide sensitive and reliable assessments of severity of ataxia in FRDA.Clinical relevance-This study presents a multiview IMU-based approach that can enhances the objective assessment of severity of ataxia in FRDA.

Reliable Objective Assessment of Friedreich Ataxia Through Isolation Forest-Based Anomaly Detection

Ranaweera K, Randeniya M, Pathirana PN, Milne SC, Horne M, Delatycki MB, Corben LA. Reliable Objective Assessment of Friedreich Ataxia Through Isolation Forest-Based Anomaly Detection. Annu Int Conf IEEE Eng Med Biol Soc. 2025 Jul;2025:1-6. doi: 10.1109/EMBC58623.2025.11253335. PMID: 41336277.

Clinical relevance- This study improves the reliability of objective Friedreich's ataxia assessments, providing clinicians with a more consistent and accurate tool for tracking disease progression and evaluating treatment effects.