This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Tendon injuries affect more than 400,000 people annually in US alone. The tendon injuries are a frustrating and devastating problem in the clinic and are critical for functional return after severe trauma, amputations, and rheumatoid arthritis. It is responsible for loss of more than 5 million workdays, and an overall economic impact of $15 billion annually. Repair ruptures or adhesion formations have been well-known problems associated with repairs of intrasynovial flexor tendons. Strengthening the repairs, decreasing rupture rate, and limiting adhesions have been a major focus of clinical and research efforts. Our preliminary studies showed that transfer of basic fibroblast growth factor (bFGF) gene through adeno-associated viral (AAV2) vectors significantly increased the strength of healing tendons 4 weeks after repairs and that AAV2-bFGF gene therapy promoted collagen synthesis. These evidences coupled with our findings that AAV2 vector elicited far less tissue reactions than adenoviral vectors and liposomes lead us to postulate that transfer of exogenous bFGF gene through AAV2 vector would drastically accelerate tendon healing process and hold a great promise to enhance strength of the lacerated intrasynovial tendons. This proposed study, based on our previous in vitro and in vivo studies, aims to optimize the dosage of AAV2-bFGF thus maximizing the effects, to investigate effects of AAV2-bFGF gene therapy over an extended period of tendon healing, and to carry out clinical trials of the gene therapy for injured digital flexor tendons.
Our specific aims will be (1) to determine the optimal doses of AAV2-bFGF injection into the tendon, (2) to investigate the changes in the strength and adhesions of the tendon at varying intervals over a critical period of time in a clinical relevant rabbit tendon laceration model, (3) to investigate persistence of transgene expression and immune responses, and (4) to produce AAV2-hbFGF and to perform clinical trials to test safety and efficiency of the proposed gene therapy for tendon repairs. Gene expression of and production of growth factors and matrix components in the tendon, biomechanics and morphology of the tendons will be included in evaluation of biological effects of this approach in animal studies. The ultimate goal of our work is to develop a novel molecular approach to treat the problem of repair ruptures and adhesion formation of the injured intrasynovial tendons which are inherently of low growth factor activities and lack adequate healing potential.
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