Methods for treating and/or limiting development of diabetes
Inventors
Berggren, Per Olof • Yang, Shao-Nian
Assignees
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Publication Number
US-9353183-B2
Publication Date
2016-05-31
Expiration Date
Abstract
The present invention provides methods for identifying candidate compounds for limiting development of and/or treating diabetes, and methods for limiting development of and/or treating diabetes.
Core Innovation
The invention relates to apolipoprotein CIII (ApoCIII) and hyperactivation of pancreatic β-cell CaV1 channels in diabetes-related mechanisms. ApoCIII increases CaV1 channel open probability and CaV1 channel density and elevates whole-cell Ca2+ currents in pancreatic β cells. The CaV1 channel blocker nimodipine abrogates the effect of ApoCIII on CaV1 hyperactivation.
The invention further describes that individual inhibition of PKA, PKC, or Src yields marginal effects, whereas combined inhibition of PKA and Src counteracts ApoCIII-driven CaV1 hyperactivation. A cocktail of PKA/PKC/Src inhibitors is also described as counteracting ApoCIII-driven CaV1 hyperactivation.
The invention includes evidence that β1 integrin knockdown prevents ApoCIII-induced CaV1 hyperactivation, supporting a β1 integrin-dependent coactivation of PKA and Src. The document also describes screening/identification aspects for candidate compounds by measuring inhibition of ApoCIII-induced increases in CaV1 density/conductivity, including controls using CaV2/CaV3 channel blockers and inhibitors of PKA/Src or β1 integrin.
Therapeutic administration concepts are outlined using PKA/Src inhibitors, β1 integrin inhibitors, and inhibitors of ApoCIII binding to pancreatic β cells. The document also includes therapeutic administration concepts that involve β1 integrin inhibitors in forms such as antibodies and inhibitors of ApoCIII binding such as antibodies/aptamers.
Claims Coverage
The partial content identifies one independent claim. The claim covers a diabetes treatment or limitation strategy by administering a combined inhibitor set targeting PKA, Src kinase, and β1 integrin expression and/or activity, with the β1 integrin component specified as an anti-β1 integrin antibody.
Combined PKA, Src kinase, and β1 integrin inhibition for diabetes
Administering to a subject in need thereof an amount effective of an inhibitor of protein kinase A (PKA), an inhibitor of Src kinase, and an inhibitor of β1 integrin expression and/or activity to treat or limit development of diabetes.
Anti-β1 integrin antibody β1 integrin inhibition
Wherein the inhibitor of β1 integrin expression and/or activity is an anti-β1 integrin antibody.
The identified independent claim covers treatment or limitation of diabetes by co-administering inhibitors of PKA and Src kinase together with an inhibitor of β1 integrin expression and/or activity, with β1 integrin inhibition specified as an anti-β1 integrin antibody.
Stated Advantages
Treat or limit development of diabetes.
Documented Applications
A method for treating diabetes or limiting development of diabetes in a subject in need thereof.
Limiting development of diabetes in subjects having or at risk of type 1 diabetes.
Limiting development of diabetes in subjects having or at risk of type 2 diabetes.
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