Developing a small peptide to control autoimmune inflammation in type diabetes

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI131784-01
Agency Tracking Number: R41AI131784
Amount: $297,387.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA16-303
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-02-15
Award End Date (Contract End Date): 2018-12-19
Small Business Information
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Principal Investigator
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Research Institution
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AURORA, CO, 80045-2570
 Nonprofit college or university
Abstract Type Diabetes T D affects an ever growing population While this disease typically has been associated with juveniles the disease in adult populations is rapidly increasing The defining clinical component is insulin loss which occurs because of sustained inflammation in the islets At present there is no means to prevent or reverse insulin loss A major inflammatory pathway in T D that contributes to insulin loss is the CD CD dyad CD is expressed on a wide array of cells and when engaged by CD creates localized inflammation This pathway is decisive in T D blocking the interaction prevents diabetes onset and reverses hyperglycemia in new onset diabetic mice A major impediment to drug development in diabetes has been the failure of therapeutics to translate from mouse to human Mindful of this we discovered that CD provides a link between mouse and human during T D We discovered that NOD mice the industry standard model for T D increase CD expression including on a sub population of T cells during diabetes development Those cells termed Th not only expand in number as diabetes develops but Th cells are singularly capable of transferring T D to scid recipients In a translational approach we discovered that Th cells become prominent in human T D patients regardless of the age HLA haplotype auto antibody status or duration of disease Like in the mouse model Th cells start at low percentages but increase as human subjects progress to T D and remain at high levels even up to years after diagnosis New onset as well as long term diabetic patients have highly expanded numbers of Th cells when compared to non autoimmune or type diabetic controls A portion of TrialNet defined Pre T D subjects also have expanded Th cell numbers suggesting that these cells become pathogenic over time depending upon CD expression Controlling CD therefore will be therapeutically advantageous Methods to control CD have relied upon monoclonal antibodies or randomly generated small organic molecules Both those options have failed clinically To address this we developed a series of peptides derived from the CD protein sequence that are designed to target CD binding sites These peptides do not function like antibodies and unlike the random generated organic molecule approach have high specificity for CD In preliminary work we determined that some of the peptides prevent diabetes onset in NOD mice and one of the peptides thus far reversed hyperglycemia in new onset diabetic mice The goals of this grant are to establish clinical parameters that will allow further development of a lead candidate for therapeutic development We propose to determine how candidate peptides impact glucose tolerance testing serum insulin levels and c peptide levels Methods to control CD CD interaction have failed because heretofore they have depended upon monoclonal antibody or randomly generated organic molecules We designed CD targeting peptides that prevent diabetes onset and reverse hyperglycemia in new onset diabetic mice

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