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Gene-edited human stem cell-derived ? cells from a patient with monogenic diabetes reverse preexisting diabetes in mice.

ABSTRACT: Differentiation of insulin-producing pancreatic ? cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived ? (SC-?) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (WFS1) in iPSCs derived from a patient with Wolfram syndrome (WS). After differentiation to ? cells with our recent six-stage differentiation strategy, corrected WS SC-? cells performed robust dynamic insulin secretion in vitro in response to glucose and reversed preexisting streptozocin-induced diabetes after transplantation into mice. Single-cell transcriptomics showed that corrected SC-? cells displayed increased insulin and decreased expression of genes associated with endoplasmic reticulum stress. CRISPR-Cas9 correction of a diabetes-inducing gene variant thus allows for robust differentiation of autologous SC-? cells that can reverse severe diabetes in an animal model.

SUBMITTER: Maxwell KG

PROVIDER: S-EPMC7233417 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Gene-edited human stem cell-derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice.

Maxwell Kristina G KG Augsornworawat Punn P Velazco-Cruz Leonardo L Kim Michelle H MH Asada Rie R Hogrebe Nathaniel J NJ Morikawa Shuntaro S Urano Fumihiko F Millman Jeffrey R JR

Science translational medicine 20200401 540

Differentiation of insulin-producing pancreatic β cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived β (SC-β) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (<i>WFS1</i>) in iPSCs derived from a patient with Wolfram syndrome (WS). Afte ...[more]

PMID: 32321868

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Project description:Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants).Learning objectivesUpon completion of this educational activity, participants should be able to.Target audienceThis continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.

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Gene-edited human stem cell-derived ? cells from a patient with monogenic diabetes reverse preexisting diabetes in mice.

Publications

Gene-edited human stem cell-derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice.

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