Gene therapy vector system

Novel APIs, medical devices and gene therapy vectors/systems are increasingly being discovered and designed based on tlieii interaction with genetic and biological networks. Tlie similarity of tlie genomes of many different species and the conservation of protein stmc-tnre and fnnction necessitates consideration of the effects on the environment and tlie biosphere. 

To circumvent this problem, vectors that are based on lentiviruses have been developed. In contrast to prototypic retroviruses, lentiviruses do not require cell division for integration. Gene-therapy vectors have been developed from a broad spectrum of lentiviruses including human immunodeficiency vims (HIV), simian and feline immunodeficiency vims as well as visna/maedi vims. The most widely used lentiviral vector system is based on HIV-1. These vectors can efficiently transduce a broad spectrum of dividing and nondividing cells including neurons, hepatocytes, muscle cells, and hematopoietic stem cells [1,2]. 

Fenske DB, MacLachlan I, Cullis PR. Stabilized plasmid-lipid particles a systemic gene therapy vector. In Phillips MI, ed. Methods in Enzymology Gene Therapy Methods. Vol. 346. San Diego, CA, U.S.A. Academic Press Inc., 2002 36-71. 

The system used to deliver the desired gene into the cells, called the gene therapy vector, may be a virus, a plasmid, or even just the naked DNA. The choice of vector is based on the difficulty of getting the gene into the cell, the amount of DNA the vector can carry, the size of the gene sequence needed to provide the correct protein, and the effects the vector may have on the body. Each type of vector has advantages and disadvantages. 

Most of today s approved biotechnology products are produced in bacteria, yeast, or mammalian cells. Newer sources currently used to manufacture clinical trial materials include insect cells, transgenic animals, and gene therapy vectors. Other potential sources include transgenic plants and nonviral delivery systems... 

Large-scale production and purification of gene therapy vectors is critical in advancing the clinical utility of this new class of medicine. Linder ideal circumstances, a highly purified vector stock should be manufactured with a relatively stable shelf-life, in a dosage form that is easy to dispense and ultimately administer to the patient. The ideal system does not cuirently exist for any of the vectors used in clinical trials. ... 

Since the OTC trial, there has been rapid advancement in vector development with marked improvements in the safety (and efficacy) of new viral delivery systems. There is also a better understanding of the immunological responses to gene therapy vectors. The adverse events in the SCID trial are more recent. They appear to be a likely result of the choice of vector (retrovirus) and the ex vivo selection strategy used to modify the affected stem cells of the SCID patients. The risk benefit ratio for gene therapy treatment of these children is still deemed favorable in light of the fact that without treatment, they would not be alive. 

D. B. Fenske, 1. Maclachlan and P. R. Cullis, Stabilised plasmid-lipid particles A systemic gene therapy vector. Methods in En-zymology Gene therapy methods, Phillips M. 1. (Ed.), 346, 36-71 (2002). 

Bromberg JS, Debruyne LA, Qin L. Interactions between the immune system and gene therapy vectors bidirectional regulation of response and expression. Adv Immunol 1998 69 353-409. 

While the administration technique and the actual gene therapy vector may seem less important than the gene being delivered, they can have a significant impact. Certain administration techniques are more effective than others and the choice of local or systemic delivery may determine the efficacy of the therapy. 

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