Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Editorial
. 2024 Dec 24;12(6):123.
doi: 10.21037/atm-24-135. Epub 2024 Nov 15.

Expanding therapeutic options for Pompe disease: a new small molecule inhibitor of glycogen synthase 1 (GYS1) shows preclinical promise in Pompe disease

Rebecca L Koch #  1 , Benjamin T Cocanougher #  1 , Jeong-A Lim  1 , Nina Raben  2 , Priya S Kishnani  1
Affiliations
Editorial

Expanding therapeutic options for Pompe disease: a new small molecule inhibitor of glycogen synthase 1 (GYS1) shows preclinical promise in Pompe disease

Rebecca L Koch et al. Ann Transl Med. .
No abstract available

Keywords: Glycogen synthase inhibition; Pompe disease; glycogen storage disease (GSD); glycogen synthase 1 (GYS1); lysosomal storage disease.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-24-135/coif). P.S.K. has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. P.S.K. has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, and Asklepios Biopharmaceutical, Inc. (AskBio). P.S.K. has equity with Maze Therapeutics and has held equity in Asklepios Biopharmaceuticals and may receive milestone payments related to that equity in the future. P.S.K. is a member of an advisory board for Sanofi Genzyme, Amicus Therapeutics, and Baebies. P.S.K. has received support for travel from Sanofi Genzyme and Amicus Therapeutics. N.R. is an employee of M6P Therapeutics, and the company was not involved in the research described in this editorial. The other authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Overview of SRT and ERT in Pompe disease skeletal muscle. (A) In healthy skeletal muscle, glucose enters the muscle fiber through the GLUT1, and it is converted to G6P, G1P, and UDP-glucose. G6P is an allosteric activator of GYS1. UDP-glucose binds first to GYG1 which forms a complex with GYS1. This leads to an elongated linear polymer of glucose that is branched by GBE1 to form soluble, branched glycogen. Glycogen is broken down in the cytosol by the actions of glycogen phosphorylase (myophosphorylase; PYGM) and debranching enzyme (AGL), as well as in the lysosome by GAA. (B) In Pompe disease, loss of GAA leads to glycogen accumulation in the lysosome. An increase in GLUT1 leads to increased G6P and free glucose in the cytosol. G6P activates GYS1, which further worsens the lysosomal storage of glycogen. (C) ERT delivers the rhGAA to the lysosomes. SRT with MZ-101 inhibits GYS1 activity, reducing the amount of glycogen produced in skeletal muscle. Created with BioRender.com. GLUT1, glucose transporter 1; G1P, glucose-1-phosphate; G6P, glucose-6-phosphate; UDP, uridine diphosphate; GYS1, glycogen synthase 1; GYG1, glycogenin 1; GBE1, glycogen branching enzyme 1; GAA, acid α-glucosidase; rhGAA, human recombinant GAA; SRT, substrate reduction therapy; ERT, enzyme replacement therapy.
See this image and copyright information in PMC

Comment on

  • Small-molecule inhibition of glycogen synthase 1 for the treatment of Pompe disease and other glycogen storage disorders.
    Ullman JC, Mellem KT, Xi Y, Ramanan V, Merritt H, Choy R, Gujral T, Young LEA, Blake K, Tep S, Homburger JR, O'Regan A, Ganesh S, Wong P, Satterfield TF, Lin B, Situ E, Yu C, Espanol B, Sarwaikar R, Fastman N, Tzitzilonis C, Lee P, Reiton D, Morton V, Santiago P, Won W, Powers H, Cummings BB, Hoek M, Graham RR, Chandriani SJ, Bainer R, DePaoli-Roach AA, Roach PJ, Hurley TD, Sun RC, Gentry MS, Sinz C, Dick RA, Noonberg SB, Beattie DT, Morgans DJ Jr, Green EM. Ullman JC, et al. Sci Transl Med. 2024 Jan 17;16(730):eadf1691. doi: 10.1126/scitranslmed.adf1691. Epub 2024 Jan 17. Sci Transl Med. 2024. PMID: 38232139 Free PMC article.

References

    1. Chien YH, Lee NC, Thurberg BL, et al. Pompe disease in infants: improving the prognosis by newborn screening and early treatment. Pediatrics 2009;124:e1116-25. 10.1542/peds.2008-3667 - DOI - PubMed
    1. Li C, Desai AK, Gupta P, et al. Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction. Genet Med 2021;23:845-55. 10.1038/s41436-020-01080-y - DOI - PMC - PubMed
    1. Cohen JL, Chakraborty P, Fung-Kee-Fung K, et al. In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompe's Disease. N Engl J Med 2022;387:2150-8. 10.1056/NEJMoa2200587 - DOI - PMC - PubMed
    1. Fastman NM, Liu Y, Ramanan V, et al. The structural mechanism of human glycogen synthesis by the GYS1-GYG1 complex. Cell Rep 2022;40:111041. 10.1016/j.celrep.2022.111041 - DOI - PubMed
    1. Marr L, Biswas D, Daly LA, et al. Mechanism of glycogen synthase inactivation and interaction with glycogenin. Nat Commun 2022;13:3372. 10.1038/s41467-022-31109-6 - DOI - PMC - PubMed