Targeting apoptosis in neurological disease using the herpes simplex virus.
Herpes Simplex Viruses type 1 (HSV-1) and 2 (HSV-2) cause central nervous system (CNS) disease ranging from benign aseptic meningitis to fatal encephalitis. In adults, CNS infection with HSV-2 is most often associated with aseptic meningitis while HSV-1 frequently produces severe, focal encephalitis associated with high mortality and morbidity. Recent studies suggested that the distinct neurological outcome of CNS infection with the two viruses may be due to their distinct modulation of apoptotic cell death: HSV-1 triggers neuronal apoptosis, while HSV-2 is neuroprotective. Apoptosis also occurs in the etiology of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Down's syndrome, and determines the loss of specific neuronal populations and the decline in cognitive functions. Notwithstanding, the therapy of these disorders may rely on the use of replication-defective HSV-1 vectors to deliver anti-apoptotic transgenes to the CNS. However, the recent discovery of a neuroprotective activity innate to the HSV-2 genome (the ICP10 PK gene) suggests that: i) ICP10 PK may constitute a novel therapeutic approach by targeting both the apoptotic cell death and the cognitive decline, and ii) HSV-2 may be more suitable than HSV-1 as a vector for targeting neuronal disease.
Perkins
Dana
D
EntreMed, Inc, Rockville, MD 20850, USA. danap@entremed.com
D000818:Animals; D017209:Apoptosis; D002490:Central Nervous System / Q000166:cytology / Q000502:physiology / Q000821:virology; D002493:Central Nervous System Diseases / Q000503:physiopathology* / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006561:Herpes Simplex / Q000503:physiopathology; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000502:physiology; D018258:Herpesvirus 2, Human / Q000235:genetics* / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism
D011506:Proteins; C100671:ICP10 protein, herpes simplex virus type 2; D012264:Ribonucleotide Reductases; D017346:Protein Serine-Threonine Kinases