Ataxia therapies: What works, what’s new, and what’s next

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The Pan American Parkinson’s Disease and Movement Disorders Congress in Houston, Texas, USA, included a plenary session dedicated to ataxia therapies. This session was originally conceived by Mario Cornejo-Olivas (Peru) and was moderated by Orlando Barsottini (Brazil) and Malco Rossi (Argentina). It provided an overview and updates on the currently used treatments, new treatments, and future treatments, including gene therapies.

What works in ataxia? Optimizing care today

In the lecture “What works in ataxia? Optimizing care today,” José Luiz Pedroso (Brazil) provided an overview of the current state of ataxia treatment, exploring proven therapies and personal experience. Ataxias remain among the most therapeutically frustrating disorders in neurology. Hundreds of trials, but very few effective improvements are observed in patients with degenerative ataxias.

Taking this into account, three main points are mandatory considering treatment of ataxias:

What are the evidence-based treatments; Symptomatic benefit vs, disease modification; What are the realistic therapeutic goals.

In this presentation, three therapeutic levels are suggested: symptomatic treatment (improve gait, speech, tremor, balance; does not change disease course); disease-modifying therapy (slows progression; preserves cerebellar network); and etiology-specific therapy (only possible in a minority of ataxia).

Etiology specific therapy and treatable ataxias include: abetalipoproteinemia (supplementation with vitamin E and A); ataxia with vitamin E deficiency: supplementation with vitamin E; cerebrotendinous xanthomatosis (CTX): chenodeoxycholic acid (CDCA); CoQ10 deficiency: supplementation with CoQ10; GLUT1 deficiency: ketogenic diet; Refsum’s disease: diet low in phytanic acid and high in calories; NPC: miglustat; Episodic ataxia: acetazolamide; secondary ataxias: Vitamin deficiency / autoimmune ataxia (Eg. Anti-GAD).

Non-cerebellar manifestations are common in patients with degenerative ataxias. Therefore, general symptomatic treatment may include: amantadine for fatigue (SCA3 and other SCAs); baclofen / tizanidine / botulinum toxin for spasticity: spastic ataxias (SCAs / SPG / ARSACS); levodopa for parkinsonism (SCA3 / SCAs / RFC1 / MAS-C); trihexyphenidyl for dystonia (SCA3 / other SCAs); clonazepam and melatonin for RBD (SCA3 / MAS-C); ciclobenzaprin, carbamazepin and gabapentin for cramps and pain (SCA3).

Rehabilitation was highlighted as a relevant therapy, and there some evidences that is usually effective to improve symptoms in patients with cerebellar ataxia. Specific training is mandatory for patients with cerebellar ataxia, and should focus on gait, proprioception, balance, coordination, postural control, trunk stability, strength and resistance, task-specific functional training, and speech therapy. In spite of positive results, there is no clear evidence that rehabilitation may change the natural history of the neurodegenerative process.

Other treatments such as non-invasive brain stimulation were also discussed, such as transcranial magnetic resonance (TMS). The positive points include: strong neurophysiological rationale, safety, non-invasive, potential synergy with rehabilitation, early signals of symptomatic benefit; and the cons include low-quality evidence, heterogeneity, protocol/outcome inconsistency, uncertain durability and cost-effectiveness. In conclusion, poor evidence has demonstrated effective results with TMS in cerebellar ataxia.

What’s new in ataxia treatments

In the lecture “What’s new in ataxia treatments,” Sergio Rodriguez-Quiroga (Argentina) explained that historically, pharmacological treatment of hereditary ataxias has been largely limited to symptomatic approaches. Today, however, we are entering a more complex and cautiously optimistic era, as recent advances suggest a meaningful shift in the treatment landscape (Ariello, 2025). The following examples illustrate this transition.

Troriluzole, targeting glutamate-mediated excitotoxicity, was evaluated across multiple SCA subtypes in a late-stage study (NCT03701399) that did not meet its primary endpoint; exploratory analyses suggested a potential benefit in SCA3, and comparisons with matched natural history cohorts indicated slower progression. Additional prospective studies are needed to define its clinical role.

Friedreich’s ataxia (FA, ATX-FXN) offers another example of the significant progress achieved over the past decade in ataxia research. Major milestones have been reached in elucidating disease pathophysiology, identifying therapeutic targets, and characterizing the natural history of the disorder. Vatiquinone, targeting oxidative stress pathways, was evaluated in the MOVE-FA study (NCT04577352). However, the pivotal trial did not meet its primary efficacy endpoints. While encouraging from a mechanistic standpoint, further studies will be needed to better define its clinical benefit. Building on this scientific progress, omaveloxolone emerged as the first disease-specific therapy for FA, marking an important step forward in the field (Indelicato, 2025). Based on the results of the MOXIe trial (Lynch, 2021) and subsequent open-label extension and long-term analyses (Lynch, 2024), omaveloxolone demonstrated improvement in neurological function compared with placebo at 48 weeks, as measured by mFARS, with longer-term data suggesting a sustained benefit and slower disease progression. Real-world experience is progressively shaping how we interpret its clinical impact and integrate it into routine practice. However, the therapeutic journey in FA is far from complete. The ongoing BRAVE study in pediatric patients (NCT06953583) marks an important step toward extending treatment to younger populations and better understanding long-term outcomes. Of importance, access and implementation vary substantially across regions. In Latin America, experience with omaveloxolone is only beginning, as approval has been granted in a limited number of countries. Learning from regions with broader clinical experience will be essential to optimize its integration into routine care.

Ataxia therapeutics are clearly evolving. The progress discussed reflects a field in transition, where mechanism-driven strategies and late-stage trials are beginning to reshape clinical practice. While important challenges remain, the field is clearly moving forward.

What’s next in ataxia treatments

In the lecture “What’s next in ataxia treatments,” Christopher Stephen (USA) recognized that we are now in the era of gene therapies for genetic movement disorders (Vázquez-Mojena, 2021; Sartorelli, 2025). This is a very exciting time, particularly as in other neurological conditions, such as spinal muscular atrophy, there have been considerable successes. However, gene therapies in the ataxias have been more challenging. The rationale for using this technology in the genetic ataxias includes addressing the root cause of these disorders and preclinical success, with robust animal models in FA and the SCAs. In many ataxias, gene silencing approaches are used, whereas in FA, this involves gene augmentation strategies.

Gene therapies relevant to the ataxias were discussed, including:

1. Antisense oligonucleotides (ASOs), where synthetic DNA or RNA hybridize with mRNA or micro RNA and prevent toxic protein production, and requires repeated administration; 2. Adenovirus associated vectors (AAVs), where AAVs deliver therapeutic genes into a cell, which is permanent, requiring a single administration; 3. RNA interference (RNAi), where small genetic sequences silence certain genes, preventing them from producing harmful protein, and require repeated administration; 4. CRISPR gene editing, where target genes are directly modified, which is also permanent.

The advantages and disadvantages of these forms of gene therapy for the ataxias were compared. A problem is that these therapies tend to require invasive administration to get the therapy to the correct regions of the brain and central nervous system, frequently involving injections into multiple sites, including intra-parenchymal (cerebral/cerebellum), intracerebroventricular, cisternal, and lumbar intrathecal injections, or a combination of these, carrying with it risks from these procedures.

The lecture also included successful cases of AAV therapy in infants with the rare metabolic ataxias GM2 gangliosidosis (Eichler, 2025) and Canavan disease (Corti, 2023). In these cases, infants have been able to live longer and with less motor impairment, and are actually making milestones in these devastating conditions. However, there has been less success when tried in older children, which has also been limited by side effects (e.g., dystonia in juvenile GM gangliosidosis). An ASO trial in Alexander disease (NCT04849741), with encouraging topline results, was mentioned. Current gene therapy clinical trials were also discussed. There are current ASO trials in the spinocerebellar ataxias, although there has been concern after the tominersen ASO trial in Huntington’s disease resulted in worsening symptoms, leading to a trial in SCA3 being stopped in 2023. In addition, AAV trials in FA were discussed, including encouraging topline data in a trial for FA cardiomyopathy (NCT05445323), which showed improved cardiac frataxin expression and left ventricular mass index.

Finally, the prospect of personalized medicine, with N of 1 trials, is becoming increasingly common (Dies, 2026). However, we have to be aware that we are in the early stages of using these potentially transformative technologies, which still carry a lot of risk; but that this will improve over time, ideally ultimately resulting in cures or highly effective treatments. But there will be multiple trials and challenges to overcome before we get there.

The session concluded with an engaging discussion with the audience, reflecting the growing interest and expectations surrounding ataxia therapies. Participants raised several thoughtful questions about the current use of emerging treatments, the development of gene-based approaches, and the challenges of translating these advances into clinical practice. Particular attention was given to barriers in Latin America, including limited access to genetic testing, delays in diagnosis, regulatory differences, and the uneven availability of newly approved therapies. These discussions highlighted the importance of international collaboration, knowledge sharing, and regional capacity building to ensure that advances in ataxia therapeutics can be implemented equitably across different healthcare settings.

The lively exchange underscored both the excitement and the caution that characterize the current moment in ataxia research, as the field continues to move toward more effective and accessible treatments.

 

References

Ariello L, Rastall D, Rosenthal L. Treatment of primary adult-onset neurodegenerative cerebellar ataxias. Neurotherapeutics. 2025 Dec 11:e00805

Corti M, Byrne B, Gessler D, et al. Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation. Mol Ther Methods Clin Dev. 2023 Jun 19:30:303-314.

Dies K, Yu T, Chamberlin N, et al. The Role of Academic Medical Centers in Personalized Experimental Therapeutic Development: Key Considerations. Neurology. 2026 Feb 10;106(3):e214610

Eichler F, Cataltepe O, Daci R, et al. Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial. Nat Med. 2025 Sep;31(9):2927-2935.

Indelicato E, Delatycki M, Farmer J, et al. A global perspective on research advances and future challenges in Friedreich ataxia. Nat Rev Neurol. 2025 Apr;21(4):204-215.

Lynch D, Chin M, Delatycki M, et al. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2021 Feb;89(2):212-225.

Lynch D, Goldsberry A, Rummey C, et al. Propensity matched comparison of omaveloxolone treatment to Friedreich's ataxia natural history data. Ann Clin Transl Neurol. 2024 Jan;11(1):4-16.

Sartorelli J, Ng J, Rahim A, et al. Genetic therapies for movement disorders - current status. J Neurol. 2025 Feb 22;272(3):220.

Vázquez-Mojena Y, León-Arcia K, González-Zaldivar Y, et al. Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and Perspectives. Mov Disord. 2021 Dec;36(12):2731-2744.