Triheptanoin treatment in ataxia-telangiectasia: the significance of innovative clinical trials targeting mitochondrial dysfunction

Ataxia-telangiectasia (A-T) is a rare genetic disorder caused by ATM gene mutations, affecting 1 in 100,000 children. It presents with progressive cerebellar ataxia, immunodeficiency, cancer predisposition, and respiratory complications, typically leading to wheelchair dependence by adolescence. Our understanding of A-T has evolved from a DNA repair disorder to a mitochondrial dysfunction disease. ATM deficiency disrupts ER-mitochondrial calcium signalling, causing mitochondrial DNA release that activates the cGAS-STING pathway and drives chronic inflammation.1, 2, 3 Triheptanoin emerged as a therapeutic candidate based on findings that its metabolite, heptanoate, corrects ER-mitochondrial dysfunction and prevents cell death in A-T cells.

The trial by Lynch et al. published in the August issue of eBioMedicine — Phase 2a/b randomised placebo-controlled dose-escalation trial of triheptanoin for Ataxia-Telangiectasia: treating mitochondrial dysfunction with anaplerosis — represents considerable progress in A-T treatment, in several aspects.⁴ Firstly, the dramatic reduction in respiratory epithelial cell death (from 60% in the placebo group to less than 20% in the treatment group) provides crucial evidence supporting this new pathological understanding. The heptanoic acid-mediated repair of ER-mitochondrial signalling, particularly normalisation of VDAC1-GRP75-IP3R1 complex function, validates the efficacy of intervention at the most upstream point of the inflammatory cascade.⁴

Further, the characterisation of two treatment-responsive biomarkers provides insight into longstanding challenges in A-T clinical research. For neurofilament light chain (NfL), the demonstration of treatment responsiveness in this study further establishes NfL not just as correlated to disease severity,⁵ but as a treatment-modifiable biomarker in A-T. The significant improvement in interferon signature gene (ISG) scores indicates that triheptanoin successfully suppresses chronic inflammation mediated by the cGAS-STING pathway.⁶

Beyond biomarker measures, significant improvements in ataxia rating scales (SARA, ICARS), enhanced speech intelligibility and swallowing safety, and improvements in pulmonary MRI perfusion defects, along with pulmonary function tests demonstrated comprehensive therapeutic effects on A-T multi-system pathology. Together, these findings provide objective evidence that fundamental disease modification, rather than mere symptomatic improvement, has been achieved. That these findings apply to a broad age range (4–37 years) is of particular importance, and contrasts markedly with the age-specific effects shown in the recently published ATTeST trial of intraerythrocytic dexamethasone, which was effective only in the 6–9 year age group, raising the possibility of complementary effects through different therapeutic mechanisms.⁷

Although gastrointestinal side effects requiring dose limitation in 38% of patients represent a clinically important challenge, additional findings from the authors' investigations provide clear directions for formulation improvements.⁴ The 8-carbon fatty acid (octanoic acid), the main component of the medium-chain triglyceride mixture used as placebo, also showed cytoprotective effects, however the 7-carbon fatty acid (heptanoic acid) demonstrated significantly superior protective effects in chronogenic cell survival assays.^4,8 This suggests the possibility of maintaining therapeutic efficacy while improving tolerability through the optimisation of carbon chain length ratios or the development of sustained-release formulations.

The Lynch et al. study further demonstrated the disease-spanning significance of endotyping approaches. The enhanced treatment responsiveness in patients with Usual Interstitial Pneumonia-like phenotypes — a pattern of progressive lung fibrosis — is extremely important from the perspective of disease classification. Nintedanib, an antifibrotic therapy approved for progressive fibrosing interstitial lung diseases, showed efficacy in the INBUILD trial by slowing lung function decline.⁹ While nintedanib and triheptanoin work through different mechanisms — nintedanib directly inhibits fibrotic pathways, whereas triheptanoin addresses upstream mitochondrial dysfunction and inflammation — both show promise for A-T lung disease. Thus, targeting different aspects of the disease process could provide complementary benefits. Considering that more than 25% of patients with A-T develop progressive interstitial lung disease, combination with established antifibrotic therapies could represent a novel therapeutic strategy for suppressing pulmonary lesion progression.

Lastly, this findings of this study establish theoretical foundations for multi-target approaches that combine with NAD + supplementation therapy and STING inhibitors currently in development.^1,2 The integration of mitochondrial function improvement, anti-inflammation, and neuroprotection also suggest the possibility of extending these therapeutic principles to neurodegenerative disease groups, including Parkinson's disease, Alzheimer's disease, and ALS.

The clinical validation of pathological understanding established through basic research, demonstration of treatment responsiveness of objective biomarkers, and suggestion of disease modifiability through multifaceted therapeutic effects together mark this study as a decisive turning point in A-T treatment development, and a successful example of mechanism-based treatment development for rare diseases.

Contributors

The author read and approved the final manuscript. All conceptualisation and writing: Osamu Onodera.

Declaration of interests

Osamu Onodera declares consulting fees from Kissei Pharmaceutical; speaker honoraria from Kyowa Hakko Kirin Co., Ltd., Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharm, Takeda, Daiichi-Sankyo, Fujifilm, Sanofi, and FP-pharm; and patents for the diagnosis of HTRA1-associated disorders.