Gene therapy continues to hold exciting promise in treating many genetic disorders and producing therapeutic gene products in vivo. While the initial notion that a single treatment can integrate the foreign transgene into the genome of the host, for instance through retroviruses, is attractive, in practice repeated treatment would be required for the majority of gene therapies. Viral vectors have been the most efficient and commonly used delivery modalities for in vivo gene transfer. However, various shortcomings of these viral vectors still leave much room for improvement. Requirement of cell mitosis for retrovirus, immunogenicity of adenovirus, and size limitation of the packaged gene in adeno-associated virus (AAV) are some of the disadvantages of the viral vectors. Although promising animal data have warranted many recent clinical trials, concerns of the long-term safety of the use of viral vectors linger. Non-viral vectors present an attractive alternative because of their non-immunogenicity. They can also satisfy many of the pharmaceutical issues better than viral vectors, such as ease of scale-up, storage stability, and quality control. Because of the low efficiency and the transient nature of gene expression, non-viral gene therapy would necessitate frequent administration by muscular or intravenous injections, the common routes for non-viral in vivo gene transfer. The invasive nature of such administration renders such therapy unattractive. The objective of this proposal is to test the hypothesis that oral gene delivery can be effective with polymeric gene carriers. We have obtained promising preliminary data that the human Factor IX (FIX) gene delivered by chitosan-DNA nanospheres through the oral route can lead to circulating FIX protein concentration in the plasma up to 120 ng/mL. We have also synthesized a series of cationic poly(phosphoester)s that show efficacy of gene transfer in the muscle and the central nervous system of murine models. We propose to identify the optimal characteristics of a polymeric gene carrier in non-viral gene transfer using mechanistic information obtained from intracellular trafficking and relevant in vitro cell culture transport models. We will then evaluate the most promising polymeric gene carriers in a rat model. It is hope that these studies will pave the way of realizing the ultimate goal of gene therapy, that of applying genes as a """"""""drug"""""""". ? ?
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