Cell-type-specific gene delivery for in vivo gene therapy

RD Dornburg, PhD

Thomas Jefferson University, Philadelphia, PA United States

The method of delivering a therapeutic gene into a patient is still one of the major obstacles towards successful human gene therapy. In the past decade, my laboratory developed cell-type-specific retroviral vectors derived from avian reticuloendotheliosis viruses (REV). We demonstrated that SNV-derived retroviral vector particles, which display the antigen binding site of an antibody (single chain antibody, scA) against a human cell surface protein enabled cell-type-specific gene delivery into human cells. Here, we report that vectors pseudotyped with the envelope protein of the neurotropic rabies virus strain N2C enable cell-type-specific gene delivery into mouse and human neurons in vitro and in vivo. Further, we initiated a series of experiments to test Theracyte implantation bags as a tool for gene delivery using retroviral vectors. The system encapsulates cells, which produce a therapeutic agent, and prevents direct contact with the tissue of the patient. TheraCyte devices were filled with retroviral packaging cells, which produced retroviral vector particles derived from REVs. In vitro experiments show that such devices release infectious retroviral vectors into the tissue culture medium for up to 4 months. When such devices were implanted subcutaneously in SCID mice, they also released infectious virus into the blood stream. There, the vectors were transported to and infected tumors, which had been induced by subcutaneous injection of tissue culture cells. Thus, the concept of a slow, continuous, long-term gene delivery with implanted packaging cells may constitute a novel and attractive approach for future in vivo human gene therapy.

KEY WORDS: gene therapy, retroviral vectors, cell-type-specific gene delivery, cancer therapy, mouse model systems.

For more information, contact

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Gene Therapy, Part 2.