DMD – ANIMAL MODELS: EP.95 Downregulation of the genetic modifier PITPNA as means of therapy in Duchenne muscular dystrophy

Abstract

We identified PITPNA as a new genetic modifier of Duchenne Muscular Dystrophy (DMD) in two exceptional mildly affected Golden Retriever Muscular Dystrophy (GRMD) dogs. Downregulation of PITPNA allowed dystrophin-deficient dogs to retain functional muscle and normal lifespan and may represent an unexplored territory for therapy. This was confirmed in our dystrophin-deficient zebrafish in which pitpna downregulation by morpholino antisense nucleotide resulted in improved muscle structure and function. In the present study, we explored different strategies that both aimed to downregulate PTPNA and prevent the muscle pathology. In dystrophin-deficient zebrafish, we developed a straightforward phenotypic drug screening assay that would be inconceivable in mouse model systems. We identified that phosphodiesterase 10A (PDE10A) inhibitors improved muscle integrity and reduced pitpna expression. The PDE10A pathway was confirmed with the use of pde10a morpholino and we combined different functional assays that showed improvement in locomotion, muscle, and vascular function as well as long-term survival in dmd zebrafish. In dystrophin-deficient mice, we are currently evaluating the potential benefit of Pitpna downregulation on muscle pathology based on two different strategies: (i) the use of PDE10A inhibitors and (ii) the use of Pitpna shRNA-AAV. Despite recent advances in dystrophin replacement strategies, there is still precedence to pursue pharmacological therapies targeting genetic modifiers that can complement dystrophin-based therapies and are independent of patients’ genetic mutations. In different animal models of DMD, downregulation of the genetic modifier PITPNA presents several reasons for there to be further studied of it as a potential DMD therapeutic via two strategies that may benefit patients.