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Title: Treatment of Sulfur Mustard Corneal Injury by Augmenting the DNA Damage Response (DDR): A Novel Approach
Sulfur mustard (SM) is a highly reactive organic chemical has been used as a chemical warfare agent and terrorist threat since WWI. The cornea is highly sensitive to SM toxicity and exposure to low vapor doses can cause incapacitating acute injuries. Exposure to higher doses can elicit persistent secondary keratopathies that cause reduced quality of life and impaired or lost vision. Despite a century of research, there are no specific treatments for acute or persistent ocular SM injuries. SM cytotoxicity emerges, in part, through DNA alkylation and double-strand breaks (DSBs). Because DSBs can naturally be repaired by DNA damage response pathways with low efficiency, we hypothesized that enhancing the HR pathway could pose a novel approach to mitigate SM injury. Here we demonstrate that a dilithium salt of adenosine diphosphoribose (INV-102) increases protein levels of p53 and Sirtuin 6, upregulates transcription of BRCA1/2, enhances gH2AX focus formation and promotes assembly of repair complexes at DSBs. Based on in vitro evidence showing INV-102 enhancement of DDR through both p53-dependent and p53-independent pathways, we next tested INV-102 in a rabbit preclinical model of corneal injury. In vivo studies demonstrate a marked reduction in the incidence and severity of secondary keratopathies in INV-102-treated eyes compared to vehicle-treated eyes when treatment was started 24 hours after SM vapor exposure. These results suggest DNA repair mechanisms are a viable therapeutic target for SM injury and suggest topical treatment with INV-102 is a promising approach for SM as well as other conditions associated with DSBs.  more » « less
Award ID(s):
2143016
PAR ID:
10484995
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Editor(s):
Greenwood-Van Meerveld, Beverley
Publisher / Repository:
Pubmed
Date Published:
Journal Name:
The Journal of pharmacology and experimental therapeutics
Volume:
388
Issue:
1
ISSN:
0022-3565
Subject(s) / Keyword(s):
chemical toxicology DNA damage DNA damage and repair Drug development
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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