Lynch Matthew, Manoy Sophie, Sly Peter D, Wainwright Claire E, Wolvetang Ernst, Feenstra John E, Dowling Jason, Ware Robert S, Patel Maharshi S, Hermith-Ramirez Diana, Vogel Adam, Preece Kahn, Zappala Tania, Dai Shuan, Webber Ann, Yeo Abrey, Subramanian Goutham, Rao Geetha, Ma Cindy S, Jose Sara, Gatei Magtouf, Xin Bowen, Sandona Nicoletta, Lewindon Peter, Sinclair Katherine G, Nayler Sam, Lavin Martin F, Coman David J
Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia; Department of Paediatrics, Wesley Medical Research, Auchenflower Brisbane, QLD, 4066, Australia; Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Saint Lucia Brisbane, QLD, 4067, Australia.
Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia; Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia.
EBioMedicine. 2025 Jul 4;118:105840. doi: 10.1016/j.ebiom.2025.105840.
Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction. A-T cells demonstrate defective endoplasmic reticulum-mitochondrial connectivity disrupting calcium homoeostasis and mitochondrial fusion, which are corrected in vitro by the triheptanoin metabolite, heptanoate.
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. The primary outcome was 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.
31 participants with A-T were enrolled aged from 4 to 37 years (median 16-years). For the maximum dose vs. placebo or no dose, significant improvements was observed for the primary outcome percent nasal cell death (mean difference (MD) = -9.7%, 95% confidence interval (CI) -16.0, 4.6). The SARA subscale kinetic function improved (MD = -5.8, 95% CI -10.4, -1.2), as did ICARS subscales gait (MD = -0.5, 95% CI -0.9, -0.1) and fine motor disturbance (MD = -2.7, 95% CI -4.3, -1.1). Speech intelligibility (MD = -12.8, 95% CI -21.2, -4.3) and swallowing safety (-0.9, 95% CI -1.6, -0.3) improved. Adverse events including abdominal pain, nausea, vomiting, and diarrhoea, requiring dose capping at 20%, were observed in 12 (38%) participants.
Improvements in mitochondrial function in A-T cells in vivo in patients occurred after triheptanoin. The biomarkers neurofilament light chain and interferon signature stimulated gene scores may allow for monitoring of disease progression and treatment response.
Funded by Medical Researcher Futures Fund Australia (GA89314), The University of Queensland, Wesley Research Institute, and BrAshA-T.
共济失调毛细血管扩张症（A-T）是一种罕见的多系统疾病，其特征为神经退行性小脑共济失调、肺部疾病、免疫缺陷、高癌症风险和线粒体功能障碍。A-T细胞表现出内质网-线粒体连接缺陷，破坏钙稳态和线粒体融合，而三庚酸甘油酯代谢物庚酸在体外可纠正这些缺陷。
我们进行了一项三庚酸甘油酯的2a/b期试验，采用三臂安慰剂对照剂量递增设计。剂量按计算热量摄入的0%、10%、20%、35%的顺序每2个月递增一次，持续12个月。主要结局是呼吸道上皮细胞中的细胞死亡。关键次要结局包括共济失调评估与评分量表（SARA）、国际合作共济失调评分量表（ICARS）、言语和吞咽功能，以及新型生物标志物的发现。
招募了31名年龄在4至37岁（中位数16岁）的A-T患者。对于最大剂量组与安慰剂组或无剂量组相比，主要结局鼻细胞死亡百分比有显著改善（平均差（MD）=-9.7%，95%置信区间（CI）-16.0，4.6）。SARA子量表的运动功能得到改善（MD=-5.8，95%CI-10.4，-1.2），ICARS子量表的步态（MD=-0.5，95%CI-0.9，-0.1）和精细运动障碍（MD=-2.7，95%CI-4.3，-1.1）也得到改善。言语清晰度（MD=-12.8，95%CI-21.2，-4.3）和吞咽安全性（-0.9，95%CI-1.6，-0.3）得到改善。12名（38%）参与者出现了包括腹痛、恶心、呕吐和腹泻在内的不良事件，需要将剂量限制在20%。
三庚酸甘油酯治疗后，患者体内A-T细胞的线粒体功能得到改善。生物标志物神经丝轻链和干扰素特征刺激基因评分可能有助于监测疾病进展和治疗反应。
由澳大利亚医学研究人员未来基金（GA89314）、昆士兰大学、卫斯理研究所和BrAshA-T资助。
