Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death.
The proto-oncogene bcl-2 is known as an anti-apoptotic gene that confers the ability to block neuronal cell death after transient ischemia. In order to examine whether the bcl-2 gene can be used for protection of ischemic brain injury, we generated adeno-associated virus (AAV) vectors capable of expressing human bcl-2. Replication-defective AAV vectors were found effectively to transfer and express bcl-2 gene in the gerbil hippocampal neurons. Transduction with AAV bcl-2 5 days before forebrain ischemia prevented the DNA fragmentation in the CA1 neurons that is commonly associated with ischemia-induced cell death. Furthermore, the application of AAV bcl-2 as late as 1 h following an ischemic insult also prevented DNA fragmentation in CA1 neurons. These results suggest that the bcl-2 protein has neuroprotective functions that inhibit ischemic cell death and demonstrate the potential of AAV bcl-2 for use in post-ischemic gene therapy in the brain. Gene Therapy (2000) 7, 1244-1249.
Department of Physiology, Jichi Medical School, Minamikawachi-machi, Tochigi, Japan.
K
K
Shimazaki
M
M
Urabe
J
J
Monahan
K
K
Ozawa
N
N
Kawai
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000098:blood supply*; D016923:Cell Death; D019254:Genes, bcl-2 / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology; D007511:Ischemia / Q000628:therapy*; D008297:Male; D009474:Neurons / Q000473:pathology; D000090063:Proto-Oncogene Mas; D014161:Transduction, Genetic