Ex Vivo Gene Transfer

For ethical reasons, children enrolled in these clinical trials have also received standard therapy of enzyme infusions, so the results of these studies have been difficult to interpret and are controversial. Nevertheless, there is some evidence that the ex vivo gene transfer approach may evoke a biological response relevant to the treatment of ADA deficiency. Such interpretations have stimulated efforts to use the ex vivo strategy for other monogenic disorders, such as familial hypercholesterolemia, hemophilia B, and Gaucher s disease. 

Dr. Alain Fisher and his research team have successfully treated two infants with XSCIDS, a severe form of SCIDS that occurs only in boys. These patients lack functional T cells and natural killer cells (NK) due to mutations in the % chain of the cytokine receptor family that recognizes interleukins (i.e., IL-2, -4, -7, -9, and -15). Ex vivo gene transfer was employed. The researchers delivered the wild-type sequence for the yc chain cytokine receptor subunit to hematopoietic stem cells isolated from these patients using a nonreplicating murine retrovirus [14,15]. 

Ex vivo gene transfer into human lymphoid progenitors results in in vivo functionally mature transduced T- and -cells. Ficara, F., Aiuti, A., Mocchetti, C., Carballido, F., Superchi, D., Deola, S., Bordignon, C., Carballido, J., Roncarolo, M. 

Van Linthout S, Madeddu P. Ex vivo gene transfer for improvement of transplanted pancreatic islet viability and function. Curr Pharm Des. 2005 11 2927-2940. 

The lack of gene expression is another potential barrier. Some systems for inducible gene expressions have proved to be effective and safe in animal models (31), but they have not yet been tested in humans. Recent advances in stem cell research provide the possibility of combining gene therapy with ex vivo gene transfer into stem cells for angiogenesis therapy, as will be discussed later, If successful, this approach may overcome most of the obstacles presented by gene therapy. 

Two basic modes of gene transfer currently exist for gene therapy products, namely ex vivo or in vivo gene transfer. Ex vivo gene transfer is achieved by... 

Koda, M., Kamada, T., Hashimoto, M., Murakami, M., Shirasawa, H., Sakao, S., Ino, H., Yoshinaga, K., Koshizuka, S., Moriya, H., and Yamazaki, M. 2007. Adenovirus vector-mediated ex vivo gene transfer of brain-derived neurotrophic factor to bone marrow stromal cells promotes axonal regeneration after transplantation in completely transected adult rat spinal cord. European Spine Journal 16 2206-2214. 

Itano H, Mora BN, Zhang W, Ritter JH, McCarthy TJ, Yew NS, Mohanakumar T, Patterson GA. Lipid-mediated ex vivo gene transfer of viral interleukin 10 in rat lung allotransplantation. J Thorac Cardiovasc Surg 2001 122 29-38. 

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