BME Seminar Series: Max Rempel, Ph.D.
Chief Scientist, LAGeT Inc.
Visiting Scientist, CIV, Optics, University of Rochester
Recent progress in musculoskeletal research has greatly benefited from the advances in molecular biology uncovering the role of specific genes in osteoarthritis (OA). In this gene-centered paradigm, OA pathogenesis results from the lack of appropriate gene expression follow cartilage injury. Therefore inducing the expression of desirable genes is critical. Unfortunately, the absence of a safe and effective gene delivery system has prohibited this approach of gene therapy for articular cartilage repair. To this end, we developed a technology that aims for safe and efficient delivery and activation of a gene of interest in a site-specific manner. This technology, termed light-activated gene transduction method (LAGT), works by irradiating the target tissue with long wave ultraviolet light (UVA) from a laser, thus inducing the host's DNA repair enzymes needed to promote recombinant adeno-associated virus (rAAV) second-strand synthesis. Subsequent rAAV infection of laser-irradiated cells leads to efficient transduction, while non-irradiated bystander cells remain untransduced.
Growth/differentiation factor 5 (GDF5) is one of the most promising for gene therapy because it is responsible for chondrogenesis during development. It has been shown previously that GDF5 could be activated in articular chondrocytes within the defect, initiating appropriate repair response. Therefore, we are conducting critical in vitro and pre-clinical experiments in a rabbit articular cartilage defects model to:
- determine the maximum dose of UVA that is not harmful to articular chondrocytes in vivo;
- determine the optimal UVA dose range for laser-activated gene transduction of articular cartilage as defined by the maximal rAAV-eGFP transduction and minimal chondrocyte apoptosis in vivo; and
- validate laser-activated GDF5 gene therapy of articular cartilage defects in a rabbit model.