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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: $1,764,501.00
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
United States
DUNS: 016344134
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 DAVID WAGNER
 (303) 929-7865
 david.wagner@ucdenver.edu
Business Contact
 DAVID WAGNER
Phone: (303) 929-7865
Email: david.wagner@ucdenver.edu
Research Institution
 UNIVERSITY OF COLORADO DENVER
 
MAIL STOP F428, ANSCHUTZ MEDICAL CAMPUS, BLDG 500
AURORA, CO 80045-2571
United States

 Nonprofit college or university
Abstract

Type 1 Diabetes (T1D) 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 T1D that contributes to insulin loss is the CD40 – CD154 dyad.
CD40 is expressed on a wide array of cells and when engaged by CD154 creates localized
inflammation. This pathway is decisive in T1D; blocking the interaction prevents diabetes onset
and reverses hyperglycemia in new onset diabetic mice. We discovered that CD40 provides a
link between mouse and human during T1D. We discovered that NOD mice increase CD40
expression, including on a sub population of T cells during diabetes development. Those cells,
termed Th40, not only expand in number as diabetes develops but Th40 cells are singularly
capable of transferring T1D to scid recipients. In a translational approach, we discovered that
Th40 cells become prominent in human T1D patients, regardless of the age, HLA haplotype,
auto-antibody status, or duration of disease. Like in the mouse model, Th40 cells start at low
percentages but increase as human subjects progress to T1D and remain at high levels even up
to 40 years after diagnosis. New onset as well as long – term diabetic patients have highly
expanded numbers of Th40 cells when compared to non-autoimmune, or type 2 diabetic
controls. A portion of TrialNet defined Pre-T1D subjects also have expanded Th40 cell numbers,
suggesting that these cells become pathogenic over time, depending upon CD40 expression.
Controlling CD40 therefore will be therapeutically advantageous. Methods to control CD40 have
relied upon monoclonal antibodies or randomly generated, small organic molecules. Both those
options have failed clinically. Importantly antibodies or Fab’ fragments have never reversed
hyperglycemia. We developed a series of peptides derived from the CD154 protein sequence
that target CD40 binding sites. These peptides do not function like antibodies and unlike the
random generated organic molecule approach, have high specificity for CD40. 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 address the mechanism(s) of action of these peptides: focusing on Th40, and CD40
expressing antigen presenting cells. Translationally, we proposed that the peptides alter human
Th40 cells, rendering them susceptible to regulation.The role of CD40 during inflammation is understood; however how to safely control CD40 – mediated auto-inflammation is not. Current approaches use dangerous monoclonal antibodies. We created a set of peptides that target CD40 directly. This grant explores the mechanism of action of those peptides in type 1 diabetes development.

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

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