951. Evaluation of HSV-Mediated Alzheimer Gene Therapy Vectors Using Novel Alzheimer Mouse Model: Applications of siRNA and Neprilysin Vectors to Adjust the Metabolic Imbalance of Aâ in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common type of dementia occurring in mid- to late-life, affecting more than 4 million individuals in the United States alone. The amyloid--protein (A), which is generated from the amyloid precursor protein (APP) by - and -secretase cleavage, is a major component of pathological plaques that accumulate in AD brains. The majority of AD patients develop the disease due to over-secretion or faulty clearance of A peptide. Thus down-regulation of the expression of A or stimulation of the A clearance process may ameliorate or potentially cure the devastating disease. As we previously have presented, we have developed replication-defective HSV-mediated gene therapy vectors to favorably adjust the metabolic imbalance of A. The first vector (QAPPi), which carries an siRNA expression cassette targeting APP gene under control of human H1 RNA polymerase III promoter, significantly lowered APP protein level compared to controls in MOI-dependent manner in vitro. The second vector (QNep), which carries Neprilysin, potent A degrading protease, produced a five fold decrease on A secretion compared to cells infected with an isogenic control virus. These results support the hypothesis that HSV-mediated APP-siRNA or Neprilysin expression may reduce A levels in vivo. To test this hypothesis in vivo, we have developed a novel in vivo mouse model using a lentivirus delivering a familial AD mutant form of APP gene (Swedish mutation). The targeted viral delivery system for modeling neurodegenerative diseases has several advantages over germline transgenic mice such as temporal control of transgene expression to avoid any developmental effect and to study aging effect, spatial control of transgene expression to target brain region associated with specific disease, and ability to deliver several transgenes. We are currently investigating the in vivo efficacy of the QAPPi and QNep vectors in the APP lentivirus model.