Towards global and long-term neurological gene therapy: unexpected transgene dependent, high-level, and widespread distribution of HSV-1 thymidine kinase throughout the CNS.
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.
Zermansky
A J
AJ
Molecular Medicine and Gene Therapy Unit, Room 1.302 Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK.
Bolognani
F
F
Stone
D
D
Cowsill
C M
CM
Morrissey
G
G
Castro
M G
MG
Löwenstein
P R
PR
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*
D004279:DNA, Viral; D013937:Thymidine Kinase