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GNE Myopathy

GNE myopathy (GNEM) previously known as Nonaka Myopathy, Hereditary Inclusion Body Myopathy (HIBM) or GNE congenital disorder of glycosylation (CDG), is an ultra-rare autosomal recessive muscle disease with no approved therapy and a prevalence of 1-6 in 1,000,000 patients world-wide, but with considerable geographic differences due to founder mutations and ethnic clusters. GNEM affects young adults and is characterised by atrophy and muscle weakness that progress within 10-20 years to severe physical disability. Although it presents in early adulthood (generally around the age of 20-30 years old) patient organisations report that some patients may recall experiencing mild symptoms as early as 15 years old and seek medical attention only after evident loss of strength.
GNEM may go undiagnosed and misdiagnosed for years due to a lack of routine laboratory testing and biomarkers and a genetic test is essential to secure the diagnosis. GNEM is caused by non-allosteric, biallelic, predominantly missense mutations (~260 variants) in the GNE gene that codes for an enzyme that is critically involved in the generation of sialic acid (Sia) in muscle cells. Deficiency of Sia production and decreased sialylation of muscle glycoproteins is a feature of GNEM and presumably the cause of muscle degeneration, although there may be, as yet undefined mechanisms.

Research Efforts

Research efforts on sialylation-increasing therapies such as ManNAc and Neu5Ac have shown low absorption and gastro-intestinal adverse effects. Research is further challenged by poorly known mechanisms of action and an absence of biomarkers to determine clinical development. ProDGNE aims to overcome these obstacles through a unique joint collaboration between Europe and Canada. ProDGNE will develop a therapy which overcomes cell permeability issues, allowing higher extracellular stability and oral supplementation with reduced concentrations.

Challenges

IT IS NOT JUST ABOUT NUMBERS

The rare incidence of disease, little funding, little patient involvement, limited preclinical models, lack of reliable biomarkers, and slow disease progression make developing therapies for GNEM complicated.

UNDERSTANDING OF THE DISEASE

Due to the bifunctional aspects of GNE, the impact of its defects have not been totally addressed and recent publications suggest that GNEM spans from a simple sialic acid deficiency, including intracellular aggregation of various proteins, to age-related post-translational modifications.

DEVELOPING SUGAR-BASED THERAPIES

Sugar-based therapies are more effective and practical when taken orally, since they are rapidly metabolised. However, they require a higher frequency and duration of dose, and they disturb the gut leading to diarrhea, flatulence, and abdominal pain/discomfort.

DESIGNING CLINICAL TRIALS IN ULTRA RARE DISEASES LIKE GNE MYOPATHY

Clinical trial designs to determine treatment efficacy need a better understanding of the disease, its natural history, priority symptoms, and pathophysiology.
To address these challenges ProDGNE will combine experts in critical fields to develop a new therapy, perform in vitro and in vivo tests using the best available models, identify novel disease biomarkers that respond to treatment, and study the functionality of GNE.

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