Developing a Small Peptide to Control Autoimmune Inflammation In Type 1 Diabetes

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42AI131784-02
Agency Tracking Number: R42AI131784
Amount: $1,000,000.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA18-575
Timeline
Solicitation Year: 2018
Award Year: 2019
Award Start Date (Proposal Award Date): 2018-12-20
Award End Date (Contract End Date): 2020-11-30
Small Business Information
3000 E 7TH AVENUE PKWY, Denver, CO, 80206-3961
DUNS: 016344134
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 DAVID WAGNER
 (303) 929-7865
 david.wagner@ucdenver.edu
Business Contact
 DAN WAID
Phone: (720) 329-1649
Email: dmw@op-t.com
Research Institution
 UNIVERSITY OF COLORADO DENVER
 MAIL STOP F428, ANSCHUTZ MEDICAL CAMPUS, BLDG 500
AURORA, CO, 80045-2571
 Nonprofit college or university
Abstract
TypeDiabetesT Daffects an ever growing populationWhile this disease typically has been associated with juvenilesthe disease in adult populations is rapidly increasingThe defining clinical component is insulin losswhich occurs because of sustained inflammation in the isletsAt present there is no means to prevent or reverse insulin lossA major inflammatory pathway in T D that contributes to insulin loss is the CDCDdyadCDis expressed on a wide array of cells and when engaged by CDcreates localized inflammationThis pathway is decisive in T Dblocking the interaction prevents diabetes onset and reverses hyperglycemia in new onset diabetic miceWe discovered that CDprovides a link between mouse and human during T DWe discovered that NOD mice increase CDexpressionincluding on a sub population of T cells during diabetes developmentThose cellstermed Thnot only expand in number as diabetes develops but Thcells are singularly capable of transferring T D to scid recipientsIn a translational approachwe discovered that Thcells become prominent in human T D patientsregardless of the ageHLA haplotypeauto antibody statusor duration of diseaseLike in the mouse modelThcells start at low percentages but increase as human subjects progress to T D and remain at high levels even up toyears after diagnosisNew onset as well as longterm diabetic patients have highly expanded numbers of Thcells when compared to non autoimmuneor typediabetic controlsA portion of TrialNet defined Pre T D subjects also have expanded Thcell numberssuggesting that these cells become pathogenic over timedepending upon CDexpressionControlling CDtherefore will be therapeutically advantageousMethods to control CDhave relied upon monoclonal antibodies or randomly generatedsmall organic moleculesBoth those options have failed clinicallyImportantly antibodies or Fabfragments have never reversed hyperglycemiaWe developed a series of peptides derived from the CDprotein sequence that target CDbinding sitesThese peptides do not function like antibodies and unlike the random generated organic molecule approachhave high specificity for CDIn preliminary work we determined that some of the peptides prevent diabetes onset in NOD mice and one of the peptidesthus farreversed hyperglycemia in new onset diabetic miceThe goals of this grant are to address the mechanism sof action of these peptidesfocusing on Thand CDexpressing antigen presenting cellsTranslationallywe proposed that the peptides alter human Thcellsrendering them susceptible to regulation The role of CDduring inflammation is understoodhowever how to safely control CDmediated auto inflammation is notCurrent approaches use dangerous monoclonal antibodiesWe created a set of peptides that target CDdirectlyThis grant explores the mechanism of action of those peptides in typediabetes development

* Information listed above is at the time of submission. *

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