Myotubular myopathy is an X-linked genetic disease affecting 1 in 50,000 newborn boys caused by mutations in the MTM1 gene encoding myotubularin a protein involved in muscle cell function. The disease is characterized by extreme muscle weakness and severe respiratory distress. 50% of affected children die before the age of 18 months, and 75% before the age of 10.
The team led by Ana Buj-Bello, Research Director at Inserm and head of the “Neuromuscular Diseases and Gene Therapy” team at Généthon, designed this gene therapy. The gene therapy consists of an adenoassociated viral vector (AAV8) delivering the MTM1 gene and demonstrated its efficacy in models of myotubular myopathy.
Of the 24 children suffering from myotubular myopathy, a very severe muscle disease, 16 can now breathe without assistance, 12 stand up on their own, and 8 can walk. However, the severe adverse effects, that caused the death of 4 children, are currently being investigated to understand their origin.
Based on the results obtained in the preclinical phases, a clinical trial was launched in 2017 led by Astellas Gene Therapies.
Twenty-four children younger than 5 years old who were suffering from myotubular myopathy and on respiratory assistance at least 22 hours a day, were treated in two cohorts: 7 at the lower dose, 17 others at the higher dose. One patient was treated in France at I-Motion (Hôpital Trousseau-Paris), the Institute of Myology’s pediatric clinical trials center.
Five years after the start of the trial, the results show that:
16 children were able to do without respiratory assistance, previously indispensable 22 hours a day, between 14 and 97 weeks after treatment
20 children could sit up for at least 30 seconds. Of these, 12 could stand up on their own and 8 could walk without support (whereas no child could do so before treatment)
4 children showing signs of pre-existing hepatobiliary pathology died. The trial has led to pause until understanding the origin of these complications
Ana Buj-Bello, Head of the “Neuromuscular Diseases and Gene Therapy” team at Généthon, Research Director at Inserm and co-author of the preclinical work that led to this clinical trial highlighted:
“I’ve devoted my entire career working on myotubular myopathy. It took years of research to imagine, design and demonstrate the efficacy of gene therapy for this very severe and complex disease. Even though we absolutely must understand the reasons for the adverse effects observed in this clinical trial, it is exceptional to see children who were known to be doomed make incredible progress thanks to this drug candidate.”
Frédéric Revah, CEO Généthon adds:
“These clinical results show both how spectacularly effective gene therapy can be, and the challenges that remain, particularly in terms of adverse effects in certain contexts. While our teams are already committed to understanding and anticipating these issues, the knowledge gained from this clinical trial, which highlights certain limitations and particular hepatic susceptibilities, is rich in lessons for the entire scientific community. I would like to salute the excellence of Ana Buj-Bello’s work, which has led to major therapeutic effects in the majority of children treated, and which represents the first potential treatment for this rare and fatal disease.”
Xavier De Mollerat Du Jeu, Senior Director R&D at Thermo Fisher Scientific is accompanied by Gianluca Pettiti, Executive Vice President and President, Life Sciences Group at Thermo Fisher Scientific and Fred Parietti, Co-Founder and CEO at Multiply Labs for this Workshop at Advanced Therapies Week 2024.
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