This is a July 2025 update on the research grant funding award to Dr. Isabelle Richard, PhD (Principal Investigator, Head of the Progressive Muscular Dystrophies Laboratory at Genethon), in collaboration with Dr Sonia Albini and Dr Edoardo Malfatti. Team Titin has funded $50,000 over two years to support the project, “Generation and characterization of skeletal muscle organoids from TTN patients’ iPSC for therapeutic screening.”
“Titinopathies are rare genetic diseases that affect the muscles. They are caused by problems with a very large and important protein in muscle cells called titin. Titin acts like a spring inside our muscles, helping them stretch and contract properly. When titin is missing or not working properly due to changes in the TTN gene (mutations), muscle health is compromised. There are many different kinds of TTN mutations, and not all of them cause the same symptoms. This makes it hard for doctors to diagnose accurately or know which treatments might help. To solve this, researchers are working to better understand how specific mutations affect muscle function.
In this study, we use an innovative and powerful method to help characterize the outcome of specific mutations. It is based on tiny, lab-grown muscles—called organoids—from real patient cells. These “muscles in a dish” allow studying mechanisms of disease using the patient’s genetic background to ultimately lead to personalized therapy.
In particular, we first generated pluripotent stem cells from 3 TTN patients’ blood samples and then, thanks to the capacity of stem cells to become specialized cells, we guided them to become muscle cells in just one week by also including fibroblasts, a population required for structural support. These cells could be shaped in a 3D shape thanks to specific biomaterials and can be subjected to muscle force assays. When tested, these patient-derived muscles didn’t contract normally when stretched, just like what happens in people with titinopathies. This showed that the lab-grown muscles successfully mimic the disease.
We tested how strong the mini-muscles were. In muscles with titin mutations, especially those with truncated proteins, the muscles needed more stretching to reach full strength and were weaker overall, especially at long stretches. One patient’s muscle was much weaker than the others, showing that more severe mutations lead to worse muscle function. Overall, these analyses show that the lab-grown muscles can reflect how serious the mutation is and may help in understanding and treating each case better.”
