Gene therapy for infectious disease chronic

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Gene Therapy for Infectious Disease Chronic infectious diseases with persistent virus expres- sion, including human immunodeficiency virus (HIV), hepatitis B, and hepatitis C, represent targets for nucleic acid-based therapies to block virus production or enhance immune responses. Many approaches have been used for gene therapy of HIV infection such as enhancing the immune response to HIV and providing gene products that suppress virus replication. One approach is to use a retrovirus to transfer the HIV gp160 envelope protein gene as a vaccine to enhance virus-specific immune responses after injection into muscle. Vaccine-type gene transfer trials may be less successful in individuals who are already immunologically impaired by HIV infection. Another approach to decrease HIV replication is to modify CD4 + T cells ex vivo to express proteins that interfere with the function of the HIV TAT or REV transcription factors. These protocols depend on persistent gene expression and long-term survival of genetically modified HIV- infected cells infused into the patient. Several hundred individuals have been involved in these trials, and the pro- tocols appear to be safe; however, sufficient data are not yet available to judge clinical efficacy. Multifactorial Diseases Many diseases can be amenable to molecular therapies by identification of therapeutics. Vascular diseases caused by thrombosis and atherosclerosis have been studied follow- ing the delivery of genes coding for angiogenic growth factors. Inflammatory diseases, such as inflammatory bowel disease, arthritis, asthma, and skin diseases, have been studied as candidates for delivery of genes that encode anti-inflammatory or immunomodulatory cyto- kines. In some trials antisense oligonucleotides designed to silence expression of pro-inflammatory cytokines are under investigation. The use of gene-based therapies for neurological disor- ders is a relatively new development. However, prelimi- nary studies using an adeno-associated virus to deliver the enzyme (glutamic acid decarboxylase) responsible for the synthesis of the neurotransmitter GABA have been very favorable. During the first year of the study, improve- ments in motor function were observed without any evi- dence of adverse events, immunological alterations, or infections. New Horizons Continued progress in the understanding of molecular mechanisms of disease will lead to the development of novel genetic-based therapies. Broad application of in vivo gene transfer for the treatment of human inherited or acquired diseases will require development of new viral or nonviral systems or a substantial improvement of exist- ing systems. Critical issues being evaluated are immuno- logical responses of gene transfer vectors, regulation of gene expression, and persistence of expression. High- efficiency approaches for repair of mutation, rather than addition to mutant genes, using homologous recombina- tion is also being actively pursued. Tailoring therapies to humans with specific genetic mutations or polymorphisms is a related area for future investigation. The application of basic principles of drug therapy continues to guide evalu- ation of novel gene therapy strategies.

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