Targeting ER stress in SEPN1-Related Myopathy through molecular chaperones

SEPN1-Related Myopathy (SEPN1-RM) is a rare genetic muscle disorder that starts in childhood. It causes muscle weakness, severe curvature of the spine (scoliosis), and problems with breathing due to weakness of the diaphragm. Unfortunately, there is currently no cure, and treatment options are limited to supportive care like physical therapy or respiratory support. Our research focuses on understanding what goes wrong in the cells of people with SEPN1-RM. We discovered that the SEPN1 protein helps protect muscle cells from stress and damage by supporting healthy communication between two important parts of the cell: the endoplasmic reticulum and mitochondria. When SEPN1 is missing, this communication breaks down, leading to energy problems in the cells and increased stress. In studies using mice without the SEPN1 gene, we found that removing another protein, called ERO1A, helped reduce the stress and improved muscle health. This suggests ERO1A plays a key role in causing symptoms of the disease. We also tested a substance called TUDCA, a drug already approved for other uses, which helps cells manage stress. When given by injection, TUDCA improved breathing muscle strength and energy production in SEPN1-deficient mice. We now plan to test whether giving TUDCA orally (by mouth) is effective, since this would be easier for patients. We will also study how the body processes the drug and look for signs in the blood that can help track disease progression and treatment response in both mice and people.