Patient-reported, psychosocial and health economic outcomes in mild to moderate Friedreich's ataxia: baseline results of the PROFA study

Grobe-Einsler M, Borel S, Buchholz M, Sayah S, Hilab R, Pierron L, Iskandar A, Humphries B, Ewenczyk C, Heinzmann A, Atencio M, Feldmann K, Maas V, Faber J, Boesch S, Indelicato E, Reetz K, Schulz JB, Bischoff AT, Klopstock T, Schöls L, Minnerop M, Timmann D, Davies EH, Klockgether T, Durr A, Xie F, Michalowsky B. Patient-reported, psychosocial and health economic outcomes in mild to moderate Friedreich's ataxia: baseline results of the PROFA study. Lancet Reg Health Eur. 2025 Dec 11;61:101552. doi: 10.1016/j.lanepe.2025.101552. PMID: 41488489; PMCID: PMC12756708. 

One hundred one patients (mean [SD]: age 35.0 [11.5]; GAA-repeat size 657 [299]; 50.5% women) were included. Activities of daily living, HRQoL, communication disabilities, and informal care utilization worsened significantly across disability stages with moderate to high effect sizes. Cognitive-affective impairments and mental well-being showed significant associations with small effect sizes. Twenty-three patients (33.3%) received formal care, while 40 (58.0%) received informal care (mean 12.2 h/week). Omaveloxolone was used by 33 patients (32.7%). Annual healthcare costs excluding Omaveloxolone were €13,620 (payer) and €32,679 (societal perspective, including informal care and productivity losses).

 

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.