Reviews Gene Transfer Therapy for Neurodegenerative Disorders Andrew Feigin, MD, and David Eidelberg, MD* Center for Neurosciences, The Feinstein Institute for Medical Research, North Shore—Long Island Jewish Health System, Manhasset, New York, USA Abstract: Recent advances in gene transfer technology have led to promising new therapies for neurodegenerative disorders. This article will review methods of gene transfer therapy and applications of these techniques to both genetic and sporadic neurodegenerative illnesses. The article will focus on Parkin- son’s disease, Huntington’s disease, and Alzheimer’s disease. Several promising gene therapy approaches to these diseases are being pursued both in animal models and in early human trials. Initial safety–tolerability results from these trials appear promising. It is therefore likely that the number of human trials of gene therapy for neurodegenerative disorders will increase over the coming years. © 2007 Movement Disorder Society Key words: gene therapy; movement disorders; Parkinson’s disease; Huntington’s disease. Gene therapy is defined as “. . . the process of inserting a gene artificially into the genome of an organism to correct a genetic defect or to add a new biologic property or function with therapeutic potential.” 1 There are two broad categories of gene therapy: (1) ex vivo—transplan- tation/implantation of cells genetically modified in the laboratory; and (2) in vivo— direct insertion of a gene into the patient’s own cells. Several approaches to in vivo gene therapy for neurodegenerative diseases are currently being pursued both in animal models and in early human clinical trials. This article will review meth- ods of gene transfer and novel approaches to in vivo gene therapy for neurodegenerative disorders, focusing on Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD). METHODS OF GENE DELIVERY Genes can be delivered to the central nervous system (CNS) through the use of viral and nonviral vectors. Many viral vectors have been developed for this purpose, each with advantages and disadvantages. In general, viral vectors are delivered directly into the CNS via a crani- otomy and are locally infused into specific neuroana- tomical locations. Nonviral vectors such as liposomes may provide a means for delivering genes without the need for a craniotomy. The choice of vector and its mechanism of delivery will depend on the specific dis- ease and its neurophysiology, and the mechanism under- lying the gene therapy. Viral Vectors Viral vectors that have been proposed for use in gene transfer therapy for neurological diseases include adeno- associated virus (AAV), lentivirus, adenovirus, and her- pes simplex virus (HSV). Of these, AAV and lentivirus have received the most attention and hold the most promise for human use. AAV is a small parvovirus that contains a 4.7-kb single strand DNA genome. 2,3 AAV can be incorporated into nondividing and dividing cells and has a preference for neurons and epithelial cells. 3 Wild-type AAV is non- pathogenic, and the AAV vector is essentially devoid of This article is part of the journal’s CME program. The CME form can be found on page 1369 and is available online at http://www. movementdisorders.org/education/activities.html *Correspondence to: Dr. David Eidelberg, The Feinstein Institute for Medical Research, North Shore—Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030. E-maidavid1@nshs.edu Received 4 April 2006; Accepted 29 December 2006 Published online 28 March 2007 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21423 Movement Disorders Vol. 22, No. 9, 2007, pp. 1223–1228 © 2007 Movement Disorder Society CME 1223