Accelerating Wound Healing through RNAi

DESCRIPTION provided by applicant The growing populations of the elderly and those with type II diabetes are at high risk for developing chronic wounds that are slow to heal Effective therapeutics to promote wound healing could significantly improve the lives of these people Normal wound healing involves a coordinated cascade of events that are stimulated in part by the hypoxia that results from injury to the vasculature at the wound site These events include angiogenesis vasculogenesis macrophage recruitment inhibition of apoptosis and the expansion and mobilization of fibroblasts and keratinocytes for re epithelializaton In chronic wounds the normal response to hypoxia is impaired and many of these cellular processes are hindered In this project we have proposed to modulate three key targets involved these processes using a combination of RNA interference RNAi and antisense approaches In Phase I we identified oligonucleotides that reduce levels of two of these targets a protein and a microRNA miRNA increase levels of downstream factors promoting angiogenesis and increase the mobility of keratinocytes One of these inhibitors uses Somagenicsandapos proprietary sshRNAandquot short synthetic hairpin RNA design which has been shown to be highly effective in treating chimeric mice infected with hepatitis C virus In Phase II we will test the effects of modulating levels of the third target which is also a miRNA and evaluate the biological effects of these oligonucleotides when used individually or in combinations in tissue culture models relevant to wound healing We will then test the in vivo efficacy of these three oligonucleotides under normal as well as compromised ischemic and diabetic wound healing conditions in mice To enhance in vivo stability and eliminate any undesirable immune stimulation all three oligonucleotides will be chemically modified In addition several different methods for delivering RNA to tissue will be evaluated for efficacy in speeding wound closure and effect on the targets of the oligonucleotides as well as downstream factors involved in wound healing This novel three pronged approach to modulating the factors involved in wound healing could represent an effective strategy for treatment of chronic wounds and potentially also acute wounds PUBLIC HEALTH RELEVANCE Therapeutics that promote rapid wound closure and healing and reduce the risk of infection would be of great benefit to patients with chronic or slow healing wounds particularly diabetics The oligonucleotide based therapeutics to be developed in this program will probably not require refrigeration and they are expected to produce relatively long lasting therapeutic effects allowing for infrequent dosing These agents could provide a significant health benefit where healing is impaired including chronic wounds pressure ulcers venous ulcers and especially diabetic ulcers for which there is enormous medical need A product that successfully promotes healing of these wounds could substantially reduce the burden of healthcare costs