Development of isogenic myoblast-based models to study the underlying mechanism of cystinotic myopathy

Cystinosis is an autosomal recessive systemic lysosomal storage disorder caused by deletion or mutation of the CTNS gene encoding cystinosin, a lysosomal cystine transporter. These mutations lead to accumulation and crystallisation of cystine in the lysosomes. While the disease initially affects the kidneys, extra-renal manifestations become a significant problem in cystinosis patients who survive kidney failure by kidney transplantation. Muscular weakness is a major concern affecting daily life and leading to life-threatening events like swallowing difficulties, aspiration and pulmonary dysfunction. While these complications affect over 80% of the untreated patients by the age of 40, recent studies have showed that despite cysteamine treatment patients still suffer from muscular dysfunction at adolescence, illustrating that cysteamine is inadequate to prevent myopathy in all patients. Moreover, the underlying molecular pathogenesis affecting the muscles in these patients still remains unknown and needs to be elucidated. In this project, I aim to generate isogenic myoblast-based cell models to study cystinotic myopathy. The resulting models are generic and instrumental in getting insight in the disease mechanism and will allow testing of novel therapies.