title: Towards global and long-term neurological gene therapy: unexpected transgene dependent, high-level, and widespread distribution of HSV-1 thymidine kinase throughout the CNS.
abstract: One of the challenges of neurological gene therapy for the treatment of chronic neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases, is achieving high levels, widespread distribution, and long-lived transgene expression in the brain. Here, following the intracerebral injection of a recombinant adenovirus (RAd) encoding herpes simplex virus type 1 thymidine kinase (HSV1-TK), we detect very high levels of HSV1-TK immunoreactivity throughout the brain both ipsilaterally and contralaterally to the injection site, for up to 12 months following vector administration. This study concludes that long-term, high-level, and anatomically distributed HSV1-TK immunoreactivity can be obtained, and that this is most likely due to transgene-specific properties, because neither the distribution nor the longevity were observed for the transgene beta-galactosidase encoded by a co-injected vector. Thus, we demonstrate that transgene expression can be achieved over widespread areas of the rodent brain, even 12 months after a single injection of first-generation adenovirus vector.
authors.affiliation: Molecular Medicine and Gene Therapy Unit, Room 1.302 Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Zermansky
authors.forename: F
authors.initials: F
authors.lastname: Bolognani
authors.forename: D
authors.initials: D
authors.lastname: Stone
authors.forename: C M
authors.initials: CM
authors.lastname: Cowsill
authors.forename: G
authors.initials: G
authors.lastname: Morrissey
authors.forename: M G
authors.initials: MG
authors.lastname: Castro
authors.forename: P R
authors.initials: PR
authors.lastname: Löwenstein
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004279:DNA, Viral / Q000032:analysis; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D016679:Genome, Viral; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D009422:Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D011917:Rats, Inbred Lew; D013937:Thymidine Kinase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D019076:Transgenes / Q000235:genetics*
chemical_list: D004279:DNA, Viral; D013937:Thymidine Kinase