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AssigneeThe Trustees of Columbia University in the City of New York
InventorsDomenico Accili, Ryotaro Bouchi
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Disclosed herein are methods involving the targeting of 5HT biosynthesis in gut insulin-negative cells to convert them into insulin-positive cells. Also disclosed are methods for treating a disease or disorder in a mammal, preferably a human, associated with impaired pancreatic endocrine function, by administering a therapeutically effective amount of an enumerated active agent that reduces the expression, biosynthesis, signaling or biological activity of serotonin or increases its degradation, wherein administering comprises delivering the agent to Gut Ins− cells in the mammal. Other embodiments of the method are directed to therapy wherein an agent that significantly reduces FOXO1 expression, biosynthesis, signaling or biological activity or increases its degradation is administered in addition to the agent that reduces serotonin, or alternatively an agent that reduces FOXO1 expression is targeted to serotonin-positive gut enteroendocrine cells.
A method comprising administering to a mammal having a disease or disorder associated with impaired pancreatic endocrine function, a therapeutically effective amount of an agent selected from the group consisting of isolated small hairpin RNA (shRNA), small interfering RNA (siRNA), antisense RNA, antisense DNA, chimeric antisense DNA/RNA, and ribozymes that is sufficiently complementary to specifically bind to a gene or mRNA encoding Foxo1 protein thereby reducing the expression, biosynthesis, signaling or biological activity of Foxo1, wherein administering comprises delivering the agent to insulin-negative, serotonin-positive enteroendocrine cells in the gut (Gut-Ins− cells) thereby producing insulin-positive cells that make and secrete biologically active insulin (Gut Ins+ cells) thereby treating the disease or disorder, and wherein the agent is targeted to serotonin-positive enteroendocrine cells.
A method for producing cells in the gut of a mammal that make and secrete biologically active insulin (Gut Ins+ cells), comprising administering to the mammal an agent selected from the group consisting of isolated small hairpin ins RNA (shRNA), small interfering RNA (siRNA), antisense RNA, antisense DNA, chimeric antisense DNA/RNA, and ribozymes that is sufficiently complementary to specifically bind to a gene or mRNA encoding Foxo1 protein thereby reducing the expression, biosynthesis, signaling or biological activity of Foxo1, wherein administering comprises delivering the agent to insulin-negative cells in the gut (Gut-Ins− cells) comprising serotonin-positive, insulin-negative enteroendocrine cells thereby producing gut cells that make and secrete biologically active insulin (Gut Ins+ cells), wherein the agent is targeted to serotonin-positive enteroendocrine cells.
Dependencies are inferred from the claim text.