Regulated protein expression for in vivo gene therapy for neurological disorders: Progress, strategies, and issues

• Main Authors: Fredric P. Manfredsson, David C. Bloom, Ronald J. Mandel
• Format: Article
• Language: English
• Published: Elsevier 2012-11-01
• Series: Neurobiology of Disease
• Subjects: Transcriptional regulation; Viral vector; In vivo gene transfer; Central nervous system; Adeno-associated virus; Lentivirus
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996112000721

The field of in vivo gene therapy has matured to the point where there are numerous clinical trials underway including late-stage clinical trials. Several viral vectors are especially efficient and support lifetime protein expression in the brain and a number of clinical trials are underway for various progressive or chronic neurological disorders including Parkinson's disease, Alzheimer's disease, and Batten's disease. To date, however, none of the vectors in clinical use have any direct way to reverse or control their transgene product in the event continued protein expression should become problematic. Several schemes that use elements within the vector design have been developed that allow an external drug or pro-drug to alter ongoing protein expression after in vivo gene transfer. The most promising and most studied regulated protein expression methods for in vivo gene transfer are reviewed. In addition, potential scientific and clinical advantages of transgene regulation for gene therapy are discussed.