Methods for identifying compounds for treating type 1 diabetes
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Publication Number
US-9062306-B2
Publication Date
2015-06-23
Expiration Date
Abstract
The present invention provides methods of identifying candidate compounds for the treatment of type I diabetes by identifying those test compounds that inhibit an apoCIII-induced increase in intracellular calcium concentration in pancreatic β cells.
Core Innovation
The document describes an apoCIII-centered mechanism in type 1 diabetes in which human apolipoprotein CIII (apoCIII) according to SEQ ID NO: 2 increases intracellular calcium concentration in pancreatic β cells, with downstream intracellular signaling effects associated with β-cell death. It further links apoCIII-driven calcium effects to modulation of voltage-gated L-type Ca2+ channel activity and enhanced Ca2+ influx in pancreatic cell responses.
Based on the apoCIII-induced increase in intracellular calcium concentration, the document provides a method for identifying candidate compounds for the treatment of type 1 diabetes. The method contacts pancreatic β cells with one or more test compounds and an amount of human apoCIII (SEQ ID NO: 2) effective to increase intracellular calcium concentration in pancreatic β cells in the absence of the one or more test compounds, and then identifies test compounds that inhibit the apoCIII-induced increase in intracellular calcium concentration as candidate compounds.
The document additionally addresses how apoCIII forms in serum relate to diagnosis and propensity for type 1 diabetes, including elevated sialylated apoCIII and specific emphasis on mono-sialylated and di-sialylated apoCIII relative to controls. It further describes therapeutic approaches that use apoCIII inhibitors to reduce the apoCIII-driven Ca2+ effect, including anti-apoCIII antibodies and nucleic-acid-based approaches such as antisense and siRNA targeting apoCIII.
Claims Coverage
The partial set includes one independent claim directed to a screening method, with dependent claims refining the biochemical form or preparation of apoCIII used in the assay. The claim coverage centers on inventive features linking apoCIII (SEQ ID NO: 2) to an intracellular calcium readout in pancreatic β cells and selecting test compounds that inhibit that apoCIII-induced calcium increase.
ApoCIII-induced calcium increase assay in pancreatic β cells
A method comprising contacting pancreatic β cells with one or more test compounds and an amount of human apolipoprotein CIII (apoCIII) according to SEQ ID NO: 2 that would be effective to increase intracellular calcium concentration in the pancreatic β cells in the absence of the one or more test compounds, to thereby enable identification of apoCIII-induced intracellular calcium increases.
Identifying candidates that inhibit apoCIII-induced intracellular calcium increase
Identifying those test compounds that inhibit an apoCIII-induced increase in intracellular calcium concentration in the pancreatic β cells, wherein such test compounds are candidate compounds for the treatment of type 1 diabetes.
Sialylated apoCIII used in the assay
The method further includes using apoCIII that is sialylated in the contacting step.
Substantially purified apoCIII used in the assay
The method is characterized in that the apoCIII is substantially purified for the contacting step.
Across the independent claim and its dependents, the inventive coverage is directed to screening candidate compounds by using apoCIII (SEQ ID NO: 2) to induce an intracellular calcium concentration increase in pancreatic β cells, and selecting test compounds that inhibit that apoCIII-induced increase; dependent coverage further specifies that apoCIII is sialylated and/or substantially purified.
Stated Advantages
Enables identification of candidate compounds for the treatment of type 1 diabetes by selecting test compounds that inhibit apoCIII-induced increases in intracellular calcium concentration in pancreatic β cells.
Supports formulation of apoCIII inhibitor approaches aimed at reducing the apoCIII-driven Ca2+ effect, including anti-apoCIII antibodies and antisense or siRNA approaches.
Provides a basis for diagnosing type 1 diabetes or propensity using elevated sialylated apoCIII levels in serum, including mono-sialylated and di-sialylated forms.
Supports selecting patients for anti-apoCIII therapy based on elevated serum apoCIII.
Documented Applications
Screening test compounds by contacting pancreatic β cells with apoCIII (SEQ ID NO: 2) to identify compounds that inhibit apoCIII-induced intracellular Ca2+ increases as candidate therapeutics for type 1 diabetes.
Therapeutically administering apoCIII inhibitors to reduce the apoCIII-driven Ca2+ effect in type 1 diabetes, including anti-apoCIII antibodies and nucleic-acid approaches such as antisense and siRNA targeting apoCIII (including apoCIII mRNA).
Diagnosing type 1 diabetes or propensity by detecting elevated sialylated apoCIII levels in serum compared to controls, with emphasis on mono-sialylated and di-sialylated apoCIII.
Selecting patients for anti-apoCIII therapy based on elevated serum apoCIII.
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