Erythropoietin (Epo)-responsive anemia is a common and debilitating complication in patients of chronic renal failure, AIDS/HIV, and cancer patients undergoing chemotherapy treatment. Current therapy for this condition involves repeated intravenous or subcutaneous injection of recombinant Epo, which, although largely effective, are both expensive and inconvenient. Therefore, there has been considerable interest in the development of clinically applicable gene-based therapies for such serum protein deficiencies. Previously, several groups have demonstrated that stable production of recombinant serum Epo can be produced in mice by a single intramuscular injection of Epo gene delivered either by adenovirus vectors or by non-viral based electroporation and gene gun techniques. Despite of these initial successes, these previous approaches have practical drawbacks (safety for viral vector and invasiveness for electroporation and gene gun) that may prevent them from widespread clinical applications. The overall objective of this proposal is to develop an ultrasound system for non-invasive delivery of plasmid DNA encoding human erythropoietin (hEpo) in skeletal muscle and to investigate the potential of ultrasound-enhanced gene therapy using a rat model with chronic renal failure.
Three specific aims are proposed: 1) development of a novel ultrasound system for gene delivery in skeletal muscle, 2) in vitro optimization of acoustic parameters for most efficient gene delivery in cultured skeletal muscle cells with minimal injury, and 3) in vivo investigation of ultrasound-enhanced Epo gene therapy using a rat model with chronic renal failure. The most unique feature of the proposed ultrasound system is its ability to control and enhance cavitation in the target tissue, which is most critical for ultrasound-mediated gene delivery in skeletal muscle. Compared to other non-viral based gene delivery techniques, ultrasound is non-invasive, safe, and the exposure can be controlled both spatially and temporally. Because of these unique advantages, the prospect of ultrasound-enhanced Epo gene therapy is very promising. Besides the potential benefit to patients associated with anemia from chronic renal failure, HIV infection, and cancer, ultrasound-mediated gene delivery may also provide a viable option for gene-based therapies where skeletal muscle can be utilized as miniature pharmacies to produce and secrete recombinant proteins of therapeutic values into the blood stream.
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