Clinical trial readiness for POLG-related mitochondrial disease and ataxia: a prospective, longitudinal study identifying sensitive and ecologically valid biomarkers (C4TR-POLG).

Mitochondria are crucial components found in most cells that generate energy from food to enable cells to function normally.“Spelling mistakes” (mutations) in the POLG gene, cause mitochondrial dysfunction and subsequently disease, in organs with high energy demands. Cerebellum, the part of the brain that regulates our balance and movement coordination, and peripheral nerves, are frequently affected in people with POLG-related mitochondrial disease. They develop ataxia, which is a medical term describing symptoms related to balance impairment and muscle incoordination, such as unsteadiness, walking difficulties and slurred speech. The symptoms of ataxia in people with POLG-related mitochondrial disease are under-researched. Clinical rating scales and questionnaires are tools clinicians commonly used to determine the ataxia’s severity. However, these subjective methods have limitations. They are not sensitive enough to detect small changes in disease progression over a short time. Given that there are many developments of new therapies for mitochondrial disease, it is vital to identify sensitive and clinically meaningful measures (trial endpoints) relevant to people with POLG-related mitochondrial disease. Balance and walking (gait) assessments may be particularly useful as clinical trial endpoints for people with POLGrelated mitochondrial disease as they have been shown to be sensitive measures in other medical conditions. Several blood tests (referred to as blood biomarkers) can potentially detect mitochondrial dysfunction and the health of nerve cells. However, they have not been specifically investigated in people with POLG-related mitochondrial disease. In this study, we plan to investigate symptoms of ataxia in people with POLG-related mitochondrial disease (aged 16- 75 years). Three study visits will be scheduled over 12 months at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Gait assessments will be performed in a specialised Gait Laboratory and home environment alongside clinical assessment tools and health questionnaires. Blood samples will be collected at each visit.