Yannan Xi

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Proof-of-Mechanism of MZE782, a Specific Inhibitor of SLC6A19 for the Treatment of CKD: Phase 1 Study in Healthy Adults

Steven Chessler, Rita Humeniuk, Susan L. Limb, Julie C. Ullman et autres

Background: SLC6A19, also known as BoAT1, is a neutral amino acid transporter expressed in the proximal tubule and small intestine that is involved in the reabsorption of amino acids from the urine and the uptake of free amino acids from the diet. …

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Coupling metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and human traits

Nora Scherer, Daniel Fässler, Oleg Borisov, Yurong Cheng et autres

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene-metabolite associations, …

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First‐in‐Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease

Julie C. Ullman, Ryan A. Dick, Daniela Linzner, Todd Minga et autres

Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α‐glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the …

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Genetic Ablation of SLC6A19 Is Protective against Kidney Damage in Mouse Models of CKD

Laura E. Sanman, Richa Sarwaikar, Amelia C. Joslin, Sheela Crasta et autres

Background: SLC6A19 is a sodium-dependent neutral amino acid transporter expressed in the small intestine and proximal tubule of the kidney. SLC6A19 has emerged as a novel target for the treatment of CKD based on analyses of large human data sets that have …

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SLC6A19 (BOAT1) Allelic Series: Loss of Function Is Associated with Improved Kidney Function

Sahar V. Mozaffari, Yannan Xi, Laura E. Sanman, Julie C. Ullman et autres

Background: Chronic kidney disease (CKD) remains a significant health burden despite recent advances in care, including development of inhibitors of the sodium-dependent glucose transporter SLC5A2 (SGLT2). A burden test incorporating predicted loss of function (pLOF) and rare missense variants (MAF <1%) identified …

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Small molecule inhibition of glycogen synthase I reduces muscle glycogen content and improves biomarkers in a mouse model of Pompe disease

Rafael Calais Gaspar, Ikki Sakuma, Ali Nasiri, Brandon T. Hubbard et autres

We investigated the effects of small molecule inhibition of glycogen synthase I (GYS1) on glucose metabolism in a mouse model of Pompe disease. GYS1 inhibition reduces abnormal glycogen accumulation and molecular biomarkers associated with Pompe disease while also improving glucose intolerance. Our …

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

Julie C. Ullman, Kevin T. Mellem, Yannan Xi, Vyas Ramanan et autres

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 …

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Correction to: Pancreatic T cell protein–tyrosine phosphatase deficiency affects beta cell function in mice

Yannan Xi, Siming Liu, Ahmed Bettaieb, Kosuke Matsuo et autres

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Quantification of peripheral blood mononuclear cell (PBMC) glycogen as a novel biomarker for therapeutic intervention in Pompe disease

Terrence F. Satterfield, Daniela Linzner, Poojan Suri, Samnang Tep et autres

Pompe disease is an inherited lysosomal disease in which there is a decrease or absence of acid alpha-glucosidase activity. This enzyme defect induces glycogen storage in different tissues, especially muscle and heart, resulting in muscle weakness, respiratory failure and heart disease. Substitutive …

Small molecule inhibition of glycogen synthase 1 restores autophagolysosomal and metabolic pathway dysfunction in a mouse model of Pompe disease

Julie C. Ullman, Yannan Xi, Kevin T. Mellem, Hanne Merritt et autres

Glucagon-receptor-antagonism-mediated β-cell regeneration as an effective anti-diabetic therapy

Yannan Xi, Benbo Song, Iris Ngan, Mark J. Solloway et autres

Type 1 diabetes mellitus (T1D) is a chronic disease with potentially severe complications, and β-cell deficiency underlies this disease. Despite active research, no therapy to date has been able to induce β-cell regeneration in humans. Here, we discover the β-cell regenerative effects …

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Substrate reduction therapy for Pompe disease: Small molecule inhibition of glycogen synthase 1 in preclinical models

Julie C. Ullman, Kevin T. Mellem, Yannan Xi, Terrence F. Satterfield et autres

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