Evaluation of Intra-Arterial Autologous Mesoangioblast Administration in Patients with m.3243A>G Mutation-Induced Mitochondrial Myopathy

The primary objective of this study is to evaluate the **effect** of three intra-arterial administrations of autologous mesoangioblasts (MABs) on the biceps brachii (BB) muscle in patients with the **m.3243A>G mutation** causing mitochondrial myopathy. This will be assessed by measuring muscle strength and fatigue in the BB muscles of both arms before and after the final MABs administration in the left arm. Additionally, the study aims to assess the safety of these three advanced therapy medicinal product (ATMP) administrations to the upper left arm by monitoring for serious adverse events (SAEs), vascular obstructions, and changes in neurological vital signs. The clinical relevance of this objective lies in its potential to improve muscle function and safety profile in patients with mitochondrial myopathy, a condition characterized by muscle weakness and fatigue.

Secondary objectives include: - Assessing muscle mass in both BB muscles before and after treatment of the left BB muscle. - Evaluating morphology, m.3243A>G mutation load, and mitochondrial respiratory capacity in muscle biopsies of the left BB muscle before the first and after the last MABs administration in the left arm.

The clinical trial involves participants diagnosed with the **m.3243A>G mutation** causing mitochondrial myopathy. The study population includes both male and female subjects, aged between 18 and 64 years. Participants are required to provide written informed consent and must have the heteroplasmic m.3243A>G mutation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The selection of the trial population is based on specific inclusion criteria, ensuring that only individuals meeting these criteria are enrolled in the study.

The clinical trial is designed to evaluate the efficacy and safety of **intra-arterial** administration of **autologous mesoangioblasts** in patients with the **m.3243A>G mutation** causing **mitochondrial myopathy**. This trial is structured as a randomized, double-blind, controlled study, with an estimated duration from November 2023 to June 2026. Participants will undergo three intra-arterial administrations of the investigational product, specifically targeting the biceps brachii muscle. The primary objective is to assess changes in muscle strength and fatigue, alongside safety parameters such as serious adverse events (SAEs), vascular obstructions, and neurological vital signs.

The trial will commence with a screening visit to confirm eligibility, which includes criteria such as age between 18-64 years, both male and female, and the presence of the heteroplasmic m.3243A>G mutation. Following successful screening, participants will be enrolled and randomized. The study involves multiple visits, including baseline assessments, three treatment visits for the administration of the investigational product, and follow-up visits at 4-6 weeks post the third administration. These follow-up visits will involve assessments using a Biodex dynamometer to measure muscle strength and fatigue, as well as monitoring for any adverse events.

The end-of-study visit will conclude the trial, where final assessments of muscle mass, morphology, mutation load, and mitochondrial respiratory capacity will be conducted through muscle biopsies. Participant involvement is expected to last until the end of the study in June 2026, unless early termination is warranted due to adverse events, withdrawal of consent, or non-compliance with study procedures. The trial is categorized as a phase I+II integrated clinical trial, ensuring a comprehensive evaluation of both efficacy and safety in this patient population.

The clinical trial involves the administration of **autologous mesoangioblasts**, a **cell suspension for injection**. The active substance in this experimental medication is **autologous muscle precursor cells**, also known as autologous skeletal muscle-derived mesoangioblasts or MABS06. These cells are derived from the patient's own muscle tissue, making them a structurally diverse substance used in cell therapy. The pharmaceutical form of the product is a cell suspension, specifically designed for **intra-arterial use**. The treatment protocol includes three administrations of the cell suspension, targeting the brachial biceps (BB) muscle in patients with the m.3243A>G mutation. The administrations are conducted in the upper left arm, with the primary objective of assessing muscle strength and fatigue before and after the final administration.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the experimental administration of autologous mesoangioblasts. The trial aims to evaluate both the efficacy and safety of the treatment, monitoring for any serious adverse events (SAEs), vascular obstructions, and changes in neurological vital signs. Participant compliance is ensured through careful monitoring of the administration schedule and adherence to the intra-arterial route of delivery. The study is conducted under the auspices of the University Hospital Maastricht, which is responsible for the production and quality control of the cell suspension used in the trial.

Efficacy in this clinical trial will be assessed by evaluating the effect of three intra-arterial administrations of autologous mesoangioblasts (MABs) on patients with the **m.3243A>G mutation**. The primary efficacy endpoints include changes in muscle strength and muscle fatigue of the treated and untreated biceps brachii muscle. These parameters will be measured using Biodex dynamometer assessments conducted at baseline and 4-6 weeks following the third administration of the advanced therapy medicinal product (ATMP). Secondary endpoints involve the evaluation of muscle mass, morphology, mutation load, and mitochondrial respiratory capacity in muscle biopsies from the treated biceps brachii muscle. The trial aims to provide comprehensive data on the therapeutic impact of the autologous cell therapy on muscle function and cellular characteristics in the target patient population.