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Development of a novel method for inhibiting diabetic retinopathy

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R42EY021943-02A1
Agency Tracking Number: R42EY021943
Amount: $1,162,410.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: N
Solicitation Number: PA14-072
Timeline
Solicitation Year: 2015
Award Year: 2015
Award Start Date (Proposal Award Date): 2015-05-01
Award End Date (Contract End Date): 2018-04-30
Small Business Information
349 TENNEY CIR
Chapel Hill, NC 27514-7805
United States
DUNS: 078880116
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 DAVID CLEMMONS
 (919) 966-4735
 endo@med.unc.edu
Business Contact
 DAVID CLEMMONS
Phone: (919) 966-4735
Email: endo@med.unc.edu
Research Institution
 UNIVERSITY OF NORTH CAROLINA SYSTEM
 
BOX 2688
CHAPEL HILL, NC 27515-2688
United States

 Nonprofit college or university
Abstract

DESCRIPTION provided by applicant The long term objective of this project study is to develop a monoclonal antibody that inhibits the progression of diabetic retinopathy Insulin like growth factor I IGF I has been implicated in both endothelial dysfunction as well as the proliferative phase of the disease but IGF I concentrations in retina are not increased During hyperglycemia IGF I activates both the PI and MAP kinase pathways in endothelial cells by an aberrant mechanism that requires tyrosine phosphorylation of the transmembrane protein SHPS and this leads to enhanced cellular sensitivity to IGF I For SHPS to be phosphorylated its extracellular domain must bind to another membrane protein integrin associated protein IAP Under normoglycemic conditions the region of IAP that binds to SHPS is cleaved but during hyperglycemia cleavage is inhibited The antibody being developed disrupts IAP SHPS association thereby inhibiting this aberrant signaling pathway Our phase studies showed that the antibody inhibited retinal capillary leakage formation of acellular capillaries and pericyte ghosts Therefore it appears that IAP SHPS association is required for retinopathy progression The studies in aim will determine if disrupting IAP SHPS results in inhibition of neovascularization A polyclonal antibody directed against amino acids in rat IAP will be injected into vitreous of hypoxemic rats and its effects on retinal neovascularization determined These studies will also determine if the antibody can arrest the progression of established changes in capillary leakage and retinal thickening in that have occurred in diabetic rats The studies in aim will pursue the most important objective humanization of the mouse monoclonal antibody that was prepared during phase Murine amino acids that could potentially cause immunogenicity will be substituted with human residues in order to prevent autoimmunization The humanized form will be tested to confirm that immunogenicity is been eliminated and that its affinity has not been reduced The cDNAs encoding the antibody will be transfected into CHO cells and a high producing cell line developed The purified protein will be tested to determine if it inhibits IGF I stimulated signaling and changes in endothelial tube formation and permeabili ty If its efficacy is retained it will be administered intraocularly to monkeys to determine the effective concentration in vitreous that inhibits retinal endothelial dysfunction These studies should definitively test the hypothesis that inhibiting IGF I actions by
inhibiting SHPS IAP association in retina cells will inhibit the pathophysiologic changes that occur in diabetic retinopathy Their successful completion will represent major progress toward the long term objective of this project the development of an antibody that can be administered to patients with diabetic retinopathy that inhibits both the early events and prevents late stage manifestations of this disease Since diabetic retinopathy is the leading cause of blindness in working age adults there is a need for new therapies that are directed toward treatment of this complication PUBLIC HEALTH RELEVANCE This proposal is directed toward the development of a humanized monoclonal antibody as a drug to be administered to patients with diabetic retinopathy Diabetic retinopathy is the leading cause of blindness in working age adults years As such it represents a significant public health problem Drugs that are currently available to treat this problem are effective in approximately of patients The drug to be developed functions by a mechanism that is different from those drugs and therefore it has the potential to improve the prognosis of this disease in of the affected patients The work that i proposed will humanize the antibody and determine if it has efficacy in a primate model of this disease state

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

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