Gene Therapy for Bleeding Disorders

Gene therapy refers to any therapy in which the therapeutic entity is a nucleic acid. Gene therapy most commonly delivers a DNA sequence, the transcription of which produces a protein to perform a therapeutic function. Other approaches have delivered RNA, short interfering RNA (siRNA), RNA aptamers, nucleases (e.g., to knock out host cell genes or to facilitate “editing” of genomic DNA), or sequences to express antigens that produce specific immunization. Considered most broadly, there are two approaches to introduce therapeutic genes. The first is to directly introduce the nucleic acid sequences of interest into the target tissue in vivo. Transfer of the nucleic acid may or may not employ a delivery vehicle, referred to as a vector. Naked DNA or RNA transfer is in general inefficient unless mediated by a virus or other vector. In nature, viruses have evolved mechanisms to enter cells and deliver their viral DNA (or RNA) to the nucleus of cells, where they hijack the host cell’s machinery to transcribe and translate the virus’ genetic payload. Dozens of viruses have been investigated as potential gene delivery vectors. The second approach is to introduce the gene of interest ex vivo into cells (whether allogeneic or autologous) in culture, expand if desired the cells that express the gene efficiently, and then introduce the cells with their transgenic payload into the host. The goal of correcting hemophilia, the most common severe bleeding disorder, has been approached using multiple variations of in vivo vectors and ex vivo cell-based strategies over the last quarter century, ultimately leading to partial correction of hemophilia B in a human clinical trial (St. Louis and Verma 1988; Palmer et al. 1989; Nathwani et al. 2011).