Gene replacement therapy to restore polyamine metabolism in a Snyder-Robinson syndrome mouse model.

Abstract

Polyamines, including putrescine, spermidine, and spermine, are organic cations essential for cell growth, proliferation, and tissue regeneration. Their levels are tightly regulated by a set of enzymes controlling their biosynthesis, catabolism, and interconversion. Dysregulation of polyamine metabolism is associated with a group of rare genetic neurodevelopmental disorders collectively known as "polyaminopathies", including Snyder-Robinson Syndrome (SRS). SRS is an X-linked recessive disorder caused by mutations in the SMS gene, which encodes the spermine synthase enzyme. The lack of spermine synthase leads to aberrant polyamine levels and neurological impairments, as observed in patients and animal models. Currently, there are no available treatment options for SRS. Due to its monogenic nature, SRS is an excellent candidate for gene replacement therapy. The recent success of Zolgensma in treating children with Spinal Muscular Atrophy and the establishment of Platform Vector Gene Therapy (Pave-GT) initiative at the National Institute of Health (NIH) offer a framework to adapt-and-apply the same gene delivery system for multiple rare disease gene therapies. This chapter outlines strategies for delivering a functional copy of the SMS gene using an adeno-associated viral (AAV) vector, as well as methods to evaluate the molecular efficacy of this approach in an SRS mouse model. Our ultimate goal is to establish a versatile platform for genetic interventions targeting SRS and other polyaminopathies.