Ataxia-Telangiectasia: Treating Mitochondrial Dysfunction with a Novel Form of Anaplerosis (A-TC7)

Abstract

Background: Ataxia-telangiectasia (A-T) is a rare multisystem disease with neurodegenerative cerebellar ataxia, lung disease, immune deficiency, cancer, and mitochondrial dysfunction. A-T cells demonstrate defective endoplasmic reticulum-mitochondrial connectivity disrupting calcium homeostasis and mitochondrial fusion, which are corrected in vitro by the triheptanoin metabolite, heptanoate.<br><br>Methods: We performed a Phase 2A/B trial of triheptanoin with a three-arm placebo-controlled dose-escalation design. Doses escalated at 2-month intervals for 12 months in the sequence 0%, 10%, 20%, 35% of calculated caloric intake. Primary outcomes were correction of mitochondrial dysfunction and cell death in respiratory epithelial cells. Key secondary outcomes included scales for assessment and rating of ataxia (SARA), international cooperative ataxia rating scale (ICARS); speech and swallowing function and novel biomarker discovery.<br><br>Findings: 31 participants enrolled aged from 4-37 years (median 16-years). Significant improvements in percent cell death were observed (p<0·001). Significant improvements were observed in the SARA (p<0·05), the ICARS (p<0·01), speech intelligibility (p<0·05), and swallowing safety (p<0·001) scales. Two biomarkers, neurofilament light chain and interferon signature gene scores, improved significantly (both p<0·01). Adverse events including abdominal pain, nausea, vomiting, and diarrhoea, requiring dose capping at 20%, were observed in n=12 (38%).<br><br>Interpretation: Improvements in mitochondrial function in A-T cells in vivo in patients occurred after triheptanoin. The novel biomarkers neurofilament light chain and interferon signature stimulated gene scores may allow for monitoring of disease progression and treatment response.