Rosenberg Jonathan B, Kaplitt Michael G, De Bishnu P, Chen Alvin, Flagiello Thomas, Salami Christiana, Pey Eduard, Zhao Lingzhi, Ricart Arbona Rodolfo J, Monette Sebastien, Dyke Jonathan P, Ballon Douglas J, Kaminsky Stephen M, Sondhi Dolan, Petsko Gregory A, Paul Steven M, Crystal Ronald G
1 Department of Genetic Medicine, Weill Cornell Medical College , New York, New York.
2 Department of Neurosurgery, Weill Cornell Medical College , New York, New York.
Hum Gene Ther Clin Dev. 2018 Mar;29(1):24-47. doi: 10.1089/humc.2017.231. Epub 2018 Mar 13.
Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.
阿尔茨海默病（AD）是一种进行性退行性神经疾病，在美国，近九分之一的老年人受其影响。人群研究表明，载脂蛋白E（APOE）变体APOE4等位基因的遗传会增加患AD的风险，而APOE2纯合子则可预防晚发性AD。据推测，通过对APOE4纯合子的中枢神经系统（CNS）进行基因改造来表达“保护性”APOE2变体，可以逆转或预防进行性神经损伤。为了在大型动物模型中评估用于AD的APOE2基因治疗的CNS分布和安全性，对编码HA标签化人APOE2 cDNA序列的AAVrh.10血清型AAVrh.10hAPOE2-HA向非人灵长类动物CNS的脑实质内、脑池内和脑室内递送途径进行了评估。为了评估在CNS中实现最广泛APOE2表达的递送途径，在载体给予APOE2 DNA、mRNA和蛋白质后2个月，评估CNS中APOE2的表达。最后，使用传统毒理学检测方法评估最佳递送途径的安全性。数据表明，虽然所有三种途径都能够在AD相关区域介导ApoE2表达，但脑池内递送AAVrh.10hAPOE2-HA以最少的侵入性手术干预安全地介导了ApoE2的广泛分布，从而为将载体介导的人APOE2递送至CNS提供了最佳策略。
