Towards Global and Long-Term Neurological Gene Therapy: Unexpected Transgene Dependent, High-Level, and Widespread Distribution of HSV-1 Thymidine Kinase throughout the CNS

• Published in: Molecular therapy Vol. 4; no. 5; pp. 490 - 498
• Main Authors: Zermansky, Adam J., Bolognani, Federico, Stone, Daniel, Cowsill, Christine M., Morrissey, Graham, Castro, Maria G., Löwenstein, Pedro R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2001; Elsevier Limited
• Subjects: Adenoviridae - genetics; Adenoviridae - physiology; adenovirus; Adenoviruses; Animals; brain; Brain - metabolism; Brain - pathology; Brain research; Cytomegalovirus; DNA, Viral - analysis; Gene Expression Regulation; Gene therapy; Genetic Therapy - methods; Genome, Viral; Herpes viruses; Herpesvirus 1, Human - enzymology; Herpesvirus 1, Human - genetics; HSV1-TK; Inflammation - metabolism; Inflammation - pathology; Kinases; Male; Morphology; Nervous System Diseases - genetics; Nervous System Diseases - metabolism; Nervous System Diseases - therapy; Rats; Rats, Inbred Lew; Thymidine Kinase - analysis; Thymidine Kinase - genetics; Thymidine Kinase - metabolism; Time Factors; transgene specific; Transgenes - genetics; United States > US; transgene specific; HSV1-TK; brain; adenovirus
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1006/mthe.2001.0479

One of the challenges of neurological gene therapy for the treatment of chronic neurodegener-ative 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 β-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.