Respiratory progression in adult Duchenne muscular dystrophy. Natural history, identification of new biomarkers and design of a predictive algorithm

The advances in the standard of care for Duchenne muscular dystrophy (DMD) have prolonged the life expectancy to the third/fourth decade, and complex medical needs are now emerging in adult DMD. Respiratory failure (RF) is one of them; nearly 70% DMD patients require non-invasive ventilation (NIV) by age 20-22 years.RF is also one of the main causes of mortality yet represents an unexplored field. The lack of a sound, long-term respiratory natural history limits the trials of disease-modifying treatments in adult DMD. The contribution of motor, respiratory, genetic factors to RF is also undetermined. Respiratory assessments (e.g. spirometry) are not feasible in subjects with impaired motor ability. Diaphragm plays a pathological role, but no measures have been validated yet. This project aims to define the respiratory progression in adults with DMD and to identify causative mechanisms and biomarkers, to develop a novel, open-source predictive algorithm. Specifically, we aim to 1. collect respiratory data from childhood to adulthood; 2. understand the role of contributors to RF and validate novel assessments; 3. combine clinical and genetic variables to create a composite severity score; 4. identify possible genetic and prognostic biomarkers; 5. design an algorithm to predict a faster/slower respiratory progression. This project will be conducted over 3 years in 13 tertiary-care Italian centres. DMD patients older than 18 years, not enrolled in interventional trials will be included. The risk of developing RF requiring NIV will be correlated with retrospective clinical and genetic information and with motor, respiratory and sleep assessments conducted prospectively. Blood samples for genome-wide association study and serum markers will be collected. The expected results will enhance a personalised clinical care and will allow translational approaches (e.g.clinical trials) in adult DMD, also applicable to other dystrophinopathies.

NOTE: The project has been approved for funding, the administrative activation procedure is still ongoing.