Gene Therapy for Infectious DiseaseChronic infectious diseases with persistent virus expres-sion, including human immunodeficiency virus (HIV),hepatitis B, and hepatitis C, represent targets for nucleicacid-based therapies to block virus production or enhanceimmune responses. Many approaches have been used forgene therapy of HIV infection such as enhancing theimmune response to HIV and providing gene productsthat suppress virus replication. One approach is to use aretrovirus to transfer the HIV gp160 envelope protein geneas a vaccine to enhance virus-specific immune responsesafter injection into muscle. Vaccine-type gene transfertrials may be less successful in individuals who are alreadyimmunologically impairedby HIV infection. Anotherapproach to decrease HIV replication is to modify CD4+T cells ex vivo to express proteins that interfere with thefunction of the HIV TAT or REV transcription factors.These protocols depend on persistent gene expressionandlong-termsurvivalofgeneticallymodifiedHIV-infected cells infused into the patient. Several hundredindividuals have been involved in these trials, and the pro-tocols appear to be safe; however, sufficient data are notyet available to judge clinical efficacy.Multifactorial DiseasesMany diseases can be amenable to molecular therapies byidentification of therapeutics. Vascular diseases caused bythrombosis and atherosclerosis have been studied follow-ing the delivery of genes coding for angiogenic growthfactors.Inflammatorydiseases,suchasinflammatorybowel disease, arthritis, asthma, and skin diseases, havebeen studied as candidates for delivery of genes thatencode anti-inflammatory or immunomodulatory cyto-kines. In some trials antisense oligonucleotides designedto silence expression of pro-inflammatory cytokines areunder 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 deliverthe enzyme (glutamic acid decarboxylase) responsible forthe synthesis of the neurotransmitter GABA have beenvery favorable. During the first year of the study, improve-ments in motor function were observed without any evi-dence of adverse events, immunological alterations, orinfections.New HorizonsContinued progress in the understanding of molecularmechanisms of disease will lead to the development ofnovel genetic-based therapies. Broad application of invivo gene transfer for the treatment of human inheritedor acquired diseases will require development of new viralor nonviral systems or a substantial improvement of exist-ing systems. Critical issues being evaluated are immuno-logical responses of gene transfer vectors, regulation ofgene expression, and persistence of expression. High-efficiency approaches for repair of mutation, rather thanaddition to mutant genes, using homologous recombina-tion is also being actively pursued. Tailoring therapies tohumans with specific genetic mutations or polymorphismsis a related area for future investigation. The application ofbasic principles of drug therapy continues to guide evalu-ation of novel gene therapy strategies.