White Matter Pathology as a Barrier to Gangliosidosis Gene Therapy.

Abstract

The gangliosidoses are a family of neurodegenerative lysosomal storage diseases that have recently seen promising advances in gene therapy. White matter deficits are well established components of gangliosidosis pathology that are now receiving more attention because they are partially refractory to correction by gene therapy. After a brief synopsis of normal myelinogenesis, this review outlines current viewpoints on the origin of white matter deficits in the gangliosidoses and potential obstacles to treating them effectively by gene therapy. Dysmyelinogenesis (failure of myelin sheaths to form properly) is proposed as the predominant contributor to white matter pathology, but precise mechanistic details are not well understood. The involvement of neuronal storage deficits may extend beyond secondary demyelination (destruction of myelin due to axonal loss) and contribute to dysmyelinogenesis. Preclinical studies in animal models of the gangliosidoses have substantially improved lifespan and quality of life, leading to the initiation of several clinical trials. However, improvement of white matter pathology has lagged behind other metrics and few evidence-based explanations have been proposed to date. Research groups in the field are encouraged to include myelin-specific investigations in future gene therapy work to address this gap in knowledge.