Details

Autor(en) / Beteiligte

• Ullman, Julie C.
• Mellem, Kevin T.
• Xi, Yannan
• Ramanan, Vyas
• Merritt, Hanne
• Choy, Rebeca
• Gujral, Tarunmeet
• Young, Lyndsay E.A.
• Blake, Kerrigan
• Tep, Samnang
• Homburger, Julian R.
• O’Regan, Adam
• Ganesh, Sandya
• Wong, Perryn
• Satterfield, Terrence F.
• Lin, Baiwei
• Situ, Eva
• Yu, Cecile
• Espanol, Bryan
• Sarwaikar, Richa
• Fastman, Nathan
• Tzitzilonis, Christos
• Lee, Patrick
• Reiton, Daniel
• Morton, Vivian
• Santiago, Pam
• Won, Walter
• Powers, Hannah
• Cummings, Beryl B.
• Hoek, Maarten
• Graham, Robert R.
• Chandriani, Sanjay J.
• Bainer, Russell
• DePaoli-Roach, Anna A.
• Roach, Peter J.
• Hurley, Thomas D.
• Sun, Ramon C.
• Gentry, Matthew S.
• Sinz, Christopher
• Dick, Ryan A.
• Noonberg, Sarah B.
• Beattie, David T.
• Morgans Jr, David J.
• Green, Eric M.

Titel

Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders

Ist Teil von

• Science translational medicine, 2024-01, Vol.16 (730)

Erscheinungsjahr

2024

Beschreibungen/Notizen

• Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role in energy homeostasis and has been proposed as a therapeutic target in multiple glycogen storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors of this enzyme. Here, we report the preclinical characterization of MZ-101, a small molecule that potently inhibits GYS1 in vitro and in vivo without inhibiting GYS2, a related isoform essential for synthesizing liver glycogen. Chronic treatment with MZ-101 depleted muscle glycogen and was well tolerated in mice. Pompe disease, a glycogen storage disease caused by mutations in acid α glucosidase (GAA), results in pathological accumulation of glycogen and consequent autophagolysosomal abnormalities, metabolic dysregulation, and muscle atrophy. Enzyme replacement therapy (ERT) with recombinant GAA is the only approved treatment for Pompe disease, but it requires frequent infusions, and efficacy is limited by suboptimal skeletal muscle distribution. In a mouse model of Pompe disease, chronic oral administration of MZ-101 alone reduced glycogen buildup in skeletal muscle with comparable efficacy to ERT. In addition, treatment with MZ-101 in combination with ERT had an additive effect and could normalize muscle glycogen concentrations. Biochemical, metabolomic, and transcriptomic analyses of muscle tissue demonstrated that lowering of glycogen concentrations with MZ-101, alone or in combination with ERT, corrected the cellular pathology in this mouse model. These data suggest that substrate reduction therapy with GYS1 inhibition may be a promising therapeutic approach for Pompe disease and other glycogen storage diseases. A small-molecule inhibitor of glycogen synthase 1 reduces muscle glycogen and corrects cellular pathology in a mouse model of Pompe disease. Pompe disease is caused by mutations in acid α glucosidase (GAA), which results in pathological accumulation of glycogen, leading to muscle atrophy. Treatment consists of enzyme replacement therapy (ERT), but the disease often progresses on treatment. Here, Ullman and colleagues developed a selective inhibitor of glycogen synthase 1 (GYS1) called MZ-101 to reduce glycogen production specifically in skeletal muscle. In a mouse model of Pompe disease, MZ-101 decreased accumulation of glycogen in skeletal muscle to amounts seen with ERT. MZ-101 was well tolerated, and the combination of GYS1 inhibition with ERT showed additive effects. These findings suggest that selective GYS1 inhibition could be a valuable addition to the treatment of Pompe disease and potentially other glycogen storage diseases. —Melissa L. Norton