Pharmacology of small molecule inhibitors of GYS1 in a mouse model of Pompe disease

Xi, Yannan; Satterfield, Terrence F.; Choy, Rebeca; Gujral, Tarunmeet; Situ, Eva; Tep, Samnang; Morton, Vivian; Yu, Cecile; Reiton, Daniel; Lin, Baiwei; Merritt, Hanne; Santiago, Pam; Espanol, Bryan; Dick, Ryan; Ullman, Julie C.; Mellem, Kevin T.; Noonberg, Sarah B.; Green, Eric M.; Morgans, David J.; Chandriani, Sanjay; Beattie, David T.

doi:10.1016/j.ymgme.2021.11.342

Cited by 2 publications

(1 citation statement)

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“…Glycogen synthase enzyme activity in Pompe mice is significantly elevated [28]. Maze therapeutics is currently making efforts to translate their preclinical findings into a phase 1/2 clinical trial using an oral GYS1 inhibitor [29][30][31].…”

Section: Substrate Reduction Therapymentioning

confidence: 99%

Therapeutic thoroughfares for adults living with Pompe disease

Schoser

Laforêt

2022

Current Opinion in Neurology

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Purpose of reviewPompe disease is caused by autosomal recessive mutations in the acid a-glucosidase gene leading to a multiorgan deficiency of the enzyme acid glucosidase alfa. To recover to a nondiseased status, a lift over a threshold of 25% acid glucosidase alfa enzyme activity is required. This update on therapeutic thoroughfares for adult Pompe disease aims to assist neuromuscular and metabolic specialists. Recent findingsWe reviewed the recent studies covering enzyme replacement therapy, gene therapy, and substrate reduction therapy in adult Pompe disease. Results of phase 3 studies and the first sets of long-term data of both novel enzyme replacement therapies, avalglucosidase alfa, and ciplaglucodsidase alfa combined with miglustat, are public. First gene therapy trials are ongoing. Substrate reduction therapy is in early transition to the clinical trial phase. We still miss dose escalation and intensification of frequency trials on enzyme replacement therapy in adults, probably suitable to echo current results in infantile and juvenile Pompe disease.

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Section: Substrate Reduction Therapymentioning

confidence: 99%

Therapeutic thoroughfares for adults living with Pompe disease

Schoser

Laforêt

2022

Current Opinion in Neurology

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Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model

Donohue,

Fitzsimmons,

Bruntz

et al. 2023

Neurotherapeutics

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Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease.

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Pharmacology of small molecule inhibitors of GYS1 in a mouse model of Pompe disease

Cited by 2 publications

References 0 publications

Therapeutic thoroughfares for adults living with Pompe disease

Therapeutic thoroughfares for adults living with Pompe disease

Gys1 Antisense Therapy Prevents Disease-Driving Aggregates and Epileptiform Discharges in a Lafora Disease Mouse Model

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