Current Status of Synthetic Vector Systems

What is the present state of synthetic gene transfer technology? Many of the originally perceived advantages of synthetic vectors are still valid, perhaps foremost being that synthetic vectors are not viruses, and as such they avoid most (but not all) of the immune complications associated with recombinant viral vectors. Although viruses have evolved over the millen nia to evade host defenses, the host has likewise evolved a sophisticated system to recognize and eliminate or neutralize foreign pathogens. Because synthetic vectors presumably do not provoke specific immune responses, in theory they could be administered repeatedly, and are therefore conducive for treating diseases requiring prolonged or even lifetime correction. However, a number of overriding limitations of synthetic vectors have so far precluded capitalizing on this important feature.

One of the most significant problems continues to be the efficiency of gene transfer, and therefore the level of transgene expression that can be realized. The best synthetic vector systems express at levels that are generally 10 to 1000-fold lower than can be generated from recombinant viral vectors. This severely reduces the number of diseases for which synthetic vectors can be expected to generate therapeutic levels of a given protein. Numerous cationic liposomes, molecular conjugates, polymeric carriers, and peptides have been synthesized that mediate efficient transduction in tissue culture cells (1,2). Electroporation and ultrasound have been reported to enhance the efficiency of naked DNA transduction in skeletal muscle and other tissues (3). Novel physical methods of gene delivery have also been developed, such as catheter-mediated delivery of plasmid DNA (pDNA) to the liver and intravascular delivery into limb muscles under pressure (Fig. 2) (4-6). These techniques can generate levels of transgene expression that are significantly higher than some viral vectors such as adeno-associated virus (AAV). However, use of these methods in a clinical setting will require a further evaluation of their practicality and safety, including studies in nonhuman primates (7). At present, synthetic gene transfer efficiency remains a significant barrier to many clinical applications, but this limitation may be overcome with improved formulations and delivery methods.

Figure 1 (A) Gene transfer vectors used in clinical trial protocols. (B) Clinical trial protocols using synthetic vectors. (Adapted from Ref. 93.)

Table 1 Clinical Trials Using Synthetic Vectors

Disease

Gene

Vector

Delivery

No. trials

Cancer

Cardiovascular disease Cystic fibrosis Bone disorders/fractures Cubital tunnel syndrome Rheumatoid arthritis Hemophilia A Canavan disease Alpha-1-antitrypsin deficiency

HLA-B7/P 2-microglobulin, IL-2,

E1A, GM-CSF, gp100, others VEGF, FGF, Del-1, others CFTR, AAT Parathyroid hormone IGF-1 HSV-TK Factor VIII Aspartoacylase AAT

Naked DNA, complex

Naked DNA, complex Complex Naked DNA Naked DNA Naked DNA Naked DNA Complex Complex

Intratumoral, intraperitoneal, gene gun Intramuscular Intranasal, aerosol Bone implant Intramuscular Intraarterial

In vitro to skin fibroblasts

Intracranial

Intranasal

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