title: Gene therapy for the nervous system: challenges and new strategies.
abstract: Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that gene-based neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Molecular Neurogenetics Unit, 13th Street, Building 149, Charlestown, MA, 02129, USA, cmaguire@mgh.harvard.edu.
authors.forename: Casey A
authors.initials: CA
authors.lastname: Maguire
authors.forename: Servio H
authors.initials: SH
authors.lastname: Ramirez
authors.forename: Steven F
authors.initials: SF
authors.lastname: Merkel
authors.forename: Miguel
authors.initials: M
authors.lastname: Sena-Esteves
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002493:Central Nervous System Diseases / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D014780:Viruses / Q000235:genetics