Gene transfer research

Friedman T, Noguchi P, and Mickelson C. The evolution of public review and oversight mechanisms in human gene transfer research Joint roles of the FDA and NIH. Curr Opin Biotechnol 2001 12 304-307. 

TABLE 36.2 Framework for application of GLP provisions to novel biologies Example for gene transfer research... 

Appendix M-III-B-2. Specific Requirements of Gene Transfer Research... 

In accordance with the Protection of Human Subjects (45 CFR Part 46), investigators should indicatehowsubjects wUlbe informed about the proposed study and the manner in which their consentwiUbe solicited.They should indicatehowtheInformedConsentdocumentmakes clear the special requirements of gene transfer research. If a proposal involves children, special attention should be paid to the Protection of Human Subjects (45 CFR Part 46), Subpart D, Additional Protections for Children Involved as Subjects in Research. 

Ronald ICScheule, Ph.D. Scientific Director, Gene Transfer Research, Genzyme Corporation, Framingham, Massachusetts, U.S.A. 

Ola Johnsborg is a research scientist. He received his Ph.D. in 2003 from the Norwegian University of Life Sciences. His Ph.D. work was on molecular mechanisms underlying regulation of bacteriocin production in Laaobacillus plantarum. Since then he has been studying horizontal gene transfer by means of competence for natural transformation in the human pathogenic bacterium Streptococcus pneumoniae. 

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]. 

The simplest nonviral gene transfer system in use for gene therapy is the injection of naked plasmid DNA (pDNA) into local tissues or the systemic circulation (88, 100). Naked DNA systems are composed of a bacterial plasmid that contains the cDNA of a reporter or therapeutic gene under the transcriptional control of various regulatory elements (101, 102). In recent years, work in several laboratories has shown that naked plasmid DNA (pDNA) can be delivered efficiently to cells in vivo either via electroporation, or by intravascular delivery, and has great prospects for basic research and gene therapy (101). Efficient transfection levels have also been obtained on direct application of naked DNA to the liver (103, 104), solid tumours (105), the epidermis (106), and hair follicles (106). 

Gene therapy offers new possibilities for the treatment of cardiovascular diseases. This area of research has focused mainly on the treatment of postangioplasty restenosis, in-stent restenosis, and vein graft thickening. First clinical trials have shown that vascular gene transfer to humans is generally safe and well tolerated. Even... 

Klueh U, Dorsky D, Kreutzer D. Use of vascular endothelial cell growth factor gene transfer to enhance implantable sensor function in vivo. Journal of Biomedical Materials Research 2003, 67A, 1076-1086. 

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. 

Between the methods of Agrobacterium and microprojectile transfer, nearly every plant species can be transformed effectively [35]. However, these methods are covered by patent claims and may result in limited transformation efficiency for some cell types. For this reason, the use of alternative gene-transfer methods is an active area of research for all cell types. Alternative gene-transfer techniques include electroporation, microinjection, liposome fusion, direct transfer into protoplasts, and laser treatment [38]. In electroporation, DNA is transferred into the cell using a high-voltage electrical pulse [39]. Standard... 

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