T.I.2: Therapeutic efforts in GNE myopathy

Abstract

GNE myopathy (also known as HIBM or DMRV) is an autosomal recessive disease due to biallelic mutations in GNE , a gene encoding for a key enzyme in sialic acid biosynthesis. It is assumed that the presence of the mutated protein (or lack of its normal activity) and muscle hyposialylation contribute to the pathophysiology of the disease. Given the putative pathophysiology several therapy approaches are being tried: 1. Metabolic bypass with- a. oral supplementation of high dose sialic acid (both as extended release and regular capsules). 48weeks results of an ongoing trial in 46 patients show clinically meaningful effect in stabilizing upper extremities muscle strength associated with increased serum levels of sialic acid (H. Lau – this meeting). b. oral ManNAc (a precursor of sialic acid). Phase 1 trial has been concluded. c. IVG which contains high sialic acid showed modest effect and was abandoned. 2. Gene therapy- a. compassionate trial in a single patient used IV liposomal delivery of GNE coupled to CMV promoter. Proof of concept for mild increased sialylation was observed. b. viral-mediated gene therapy. A platform for human therapy trial has been developed based on AAV8 harboring the wild type human GNE and driven by MCK promoter. Single IV injection of this construct proved safe and resulted in human GNE expression in normal mice (Mitrani Rosenbaum – this meeting). Now that therapies are under investigation, it is critical that patients with GNE myopathy should be identified at the early stages of the disease. Disclosure: ZA is a consultant for Ultragenyx and Bioblast pharma.