Finding pharmacological treatments for Tubular Aggregate Myopathy

Tubular aggregate myopathy is an hereditary ultra-rare disease that affects women and men alike. It is characterized by muscle weakness, cramps and coagulation defects that can lead to important bleeding events. The mutations leading to this disorder are known and may reside on one of three different genes: Orai1, STIM1 or calsequestrin. A number of mutations on these genes lead to this disorder, and this accounts for the heterogeneity of the disease in different subjects, although symptoms are usually manifest at a young age and significantly reduce the quality of life of those affected. The present study is preclinical (i.e. it does not directly study subjects affected by the disorder) and is aimed at (i) chartacterizing the cellular effects of the mutation on the Orai1 and STIM1 genes. In other words, it investigates how these mutations lead to a malfunctioning of muscles and platelets; ( ii) characterizing a mouse model bearing one of these mutations (I115F), to study the natural history of the disease in rodetns; (iii) developing new molecules and testing drugs on the market to evaluate their ability to prevent or reduce the cellular defects and the symptoms in the mouse model. To increase the possibility that these findings may eventually lead to a drug for patients, these new molecules are also evaluated for their suitability for human use. The experimental plan is paralleled by interactions with clinical centers that take care of patients affected by tubular aggregate myopathy to establish the natural history of the disease, which given the heterogeneity is at present unclear, and with other international research centers. These interactions increase the likelihood that an effective drug therapy may be offered to patients in the future.