Novel therapeutic approaches to target GNE Myopathy

• Applicant: Professor Dr. Rüdiger Horstkorte
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery ; Biochemistry ; Toxicology, Laboratory Medicine
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460683975

GNE myopathy (GNEM) is a rare adult-onset severely debilitating muscle disease which affects 1 to 9:1,000,000 people among all ethnicities. GNEM is characterised by atrophy and weakness of skeletal muscles, resulting in severe incapacity and loss of quality of life within 10 to 20 years following onset. It is caused by mutations in the GNE gene, which encodes a bifunctional enzyme required for sialic acid biosynthesis, and results in hypo-sialylation in muscle tissue. There are no approved therapies and research efforts on sialylation-increasing therapies such as ManNAc and Neu5Ac have shown low absorption and high 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 among European and Canadian experts in clinical GNEM, sialic acid, organic synthesis, and -OMICS. We developed a prodrug that, when processed within cells, becomes an active therapy, increasing sialic acid in GNEM patient cells and demonstrating a higher stability when compared to clinically tested drugs. The ProDGNE consortium aims to perform proof of principle studies fostering the development of innovative therapeutic compounds for GNEM. Compound efficacy will be tested in vitro in patient derived cells and in vivo in GNEM animal models that replicate the pathology. Moreover, the mechanism of action, safety, and potential off-target will be assessed as well as post-translational modifications and ‘OMIC’ biomarkers to be utilized to monitor efficacy. The consortium will meet regulatory milestones and work closely with clinical and patient partners to have a lead compound ready to enter clinical trials at the end of the 3-year project and to address the major IRDiRC objective to develop therapies for Rare Diseases.

• DFG Programme: Research Grants
• International Connection: Canada, Italy, Portugal
• Cooperation Partners: Professor Dr. Pierluigi Caboni; Professor Dr. Hanns Lochmüller; Professorin Dr. Paula Videira