Validation of a Negative Regulator as a Novel Therapy for Autoimmune Disease

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$600,000.00
Award Year:
2012
Program:
STTR
Phase:
Phase I
Contract:
1R41AI100418-01
Award Id:
n/a
Agency Tracking Number:
R41AI100418
Solicitation Year:
2012
Solicitation Topic Code:
NIAID
Solicitation Number:
PA11-097
Small Business Information
16 CAVENDISH CT, LEBANON, NH, -
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
967719241
Principal Investigator:
RANDOLPHNOELLE
(603) 653-9908
randolph.j.noelle@dartmouth.edu
Business Contact:
GAYLEGOSSELIN
(603) 493-5390
gbg@immunext.com
Research Institute:
DARTMOUTH COLLEGE

DARTMOUTH COLLEGE
Office of Sponsored Projects 11 Rope Ferry Rd. #6210
HANOVER, NH, 03755-
() -

Abstract
DESCRIPTION (provided by applicant): The immune system depends upon an exquisite balance between positive and negative signals to maintain proper function. However, disruptions of this balance can lead to inappropriate responses: for example loss of negative regulation can result in autoimmunity. VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation), is a recently identified negative checkpoint regulator of immune function. Studies in multiple cancer models have shown that blockade of VISTA dependent signals leads to enhanced tumor immunity. Additionally, in a model of experimental allergic encephalomyelitis (EAE), blockade of VISTA resulted in early disease onset and enhanced severity. These findings suggest that VISTA expression is animportant regulator of immunity and modulation of this pathway could lead to the development of novel therapeutics for the treatment of autoimmunity. With nearly 50 million people suffering from autoimmune diseases in the US alone, and with treatment costsprojected to be over 100B/yr, development of safe, effective therapies is an utmost priority. VISTA has been validated as a negative regulator in the murine system. The goal of this proposal is to confirm that VISTA also functions as negative regulator of human immunity. Studies will determine VISTA expression on both lymphocyte and myeloid populations. Functional studies will determine the effects of VISTA dependent signals on T cell proliferation, effector function and differentiation. The studies also will evaluate whether VISTA may regulate the function of other immune cells providing valuable insights on where therapies modulating the VISTA pathway may have the greatest therapeutic potential. Insoluble forms of VISTA-Ig have been shown to inhibit T cell responses in vivo. These results demonstrate that engagement of the currently undefined receptor leads to modulation of immunity. We will develop multimeric soluble forms of VISTA-Ig as potential therapeutic agents. We will test them in vitro for the ability to modulate T cell responses. Agonists targeted to the VISTA pathway could be used to treat a variety of human autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. Because of the compelling unmet need, the documented activity of VISTA in EAE, and our experience in the development of drugs in MS, we chose MS as the first indication to develop. After meeting the success criteria for this Phase 1 STTR, the Phase 2 STTR program will develop the lead VISTA agonist as an immunosuppressive drug to treat relapsing/remitting MS. PUBLIC HEALTH RELEVANCE: VISTA is a recently identified negative checkpoint regulator of immune function. Studies in murine models have demonstrated that blockade of VISTA dependent signals can enhance autoimmunity. This project will characterize VISTA expression and function in the human immune system and test soluble mutlimeric forms of VISTA-Ig as agonistic agents. We believe engagement of the VISTA pathway has the potential to be harnessed as a novel treatment for a wide range of autoimmune diseases, including Multiple Sclerosis.

* information listed above is at the time of submission.

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