Chapter 065. Gene Therapy in Clinical Medicine (Part 5) Other Diseases The power and versatility of gene transfer approaches are such that there are few serious disease entities for which gene transfer therapies are not under development. Besides those already discussed, other areas of interest include gene therapies for HIV and for neurodegenerative disorders. The latter include studies in patients with Parkinson's disease, where AAV vectors expressing enzymes required for enhanced production of dopamine, or of the inhibitory neurotransmitter γ-aminobutyric acid, have been introduced into affected areas of the brain (striatum, subthalamic nucleus) by stereotactic neurosurgery. In Alzheimer's disease, an ex vivo approach in which autologous fibroblasts are transduced with a retroviral vector expressing nerve growth factor, then reimplanted into the basal forebrain, has slowed the rate of cognitive decline in a small Phase I study. Summary The development of new classes of therapeutics typically takes two to three decades; monoclonal antibodies and recombinant proteins are recent examples. Gene therapeutics, which entered clinical testing in the early 1990s, are well along in the course of development, and are likely to become increasingly important as a therapeutic modality in the twenty-first century. A central question to be addressed is the long-term safety of gene transfer, and regulatory agencies have mandated a 15-year follow-up for subjects enrolled in gene therapy trials (Table 65-3). Realization of the therapeutic benefits of the Human Genome Project, and of new discoveries such as RNAi, will depend on continued progress in gene transfer technology. Table 65-3 Taking History from Subjects Enrolled in Gene Transfer Studies Elements of History for Subjects Enrolled in Gene Transfer Trials 1. What vector was administered? Is it predominantly integrating [retroviral, lentiviral, herpesvirus (latency and reactivation)], or non- integrating (plasmid, adenoviral, AAV)? 2. What was the route of administration of the vector? 3. What was the target tissue? 4. What gene was transferred in? A disease-related gene? A marker? 5. Were there any adverse events noted after gene transfer? Screening Questions for Long-Term Follow- Up in Gene Transfer Subjects a 1. Has a new malignancy been diagnosed? 2. Has a new neurologic/ophthalmologic disorder, or exacerbation of a pre- existing disorder, been diagnosed? 3. Has a new autoimmune or rheumatologic disorder been diagnosed? 4. Has a new hematologic disorder been diagnosed? a Factors influencing long-term risk include: integration of the vector into the genome; vector persistence without integration; and transgene-specific effects Acknowledgment I would like to thank Valder Arruda, MD, PhD, for his review of the manuscript Further Readings Hacein-Bey-Abina S et al: LMO2- associated clonal T cell proliferation in two patients after gene therapy for SCID- XI. Science 302:415, 2003 [PMID: 14564000] Lin E, Nemunaitis J: Oncolytic viral therapies. Cancer Gene Ther 11:643, 2004 [PMID: 15286681] Manno CS et al: Successful transduction of liver in hemophilia by AAV- Factor IX and limitations imposed by the host immune response. Nat Med 12:342, 2006 [PMID: 16474400] Sadelain M et al: Targeting tumours with genetically enhance d T lymphocytes. Nat Rev Cancer 3:35, 2003 [PMID: 12509765] Shah PB, Losordo DW: Non- viral vectors for gene therapy: Clinical trials in cardiovascular disease. Adv Genet 54:339, 2005 [PMID: 16096018] Skarlatos SI: New programs for gene- and cell-based therapies at NHLBI. Clin Pharmacol Ther 82:334, 2007 [PMID: 17625516] Gene Therapy Clinical Trials Worldwide. J Gene Med, New Jersey, Wiley, 2006 www.abedia.com/wiley/indications.php . Chapter 065. Gene Therapy in Clinical Medicine (Part 5) Other Diseases The power and versatility of gene transfer approaches are such that there. recombinant proteins are recent examples. Gene therapeutics, which entered clinical testing in the early 1990s, are well along in the course of development, and are likely to become increasingly. Taking History from Subjects Enrolled in Gene Transfer Studies Elements of History for Subjects Enrolled in Gene Transfer Trials 1. What vector was administered? Is it predominantly integrating