Departments of Pathology and Laboratory Medicine, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA.
Mol Ther. 2011 Nov;19(11):2012-20. doi: 10.1038/mt.2011.151. Epub 2011 Aug 2.
Many genetic metabolic diseases manifest in infancy, therefore, it is important to develop effective treatments that could be implemented at this time. Adeno-associated virus serotype 8 (AAV8) gene transfer has been studied in neonatal mouse, cat, and dog models and shown some efficacy with a single hepatic injection at birth. AAV8-mediated liver gene transfer has also generated sustained therapeutic effects in feline and canine models of lysosomal storage disorders. In these models, delaying the age of vector treatment increased gene transfer stability. The growth rate of infant nonhuman primates is more similar to the growth trajectory of humans, thus infant monkeys provide an excellent model to study AAV gene transfer efficiency, stability, and safety. In this study, we report for the first time that AAV8-mediated hepatic gene transfer in infant monkeys is safe and efficient but less stable when compared to adolescent animals. Infant monkeys administered AAV8 intravenously at 1 week postnatal age achieved up to 98% transduction of hepatocytes within 7 days of injection; however, there was significant dilution of genomes and loss of transgene expression 35 days postadministration. Delaying the injection to 1 month postnatal age did not improve stability of transduction but decreased the antibody response to AAV8 capsid.
许多遗传性代谢疾病在婴儿期就有表现，因此，开发能够在此时实施的有效治疗方法非常重要。腺相关病毒血清型 8（AAV8）基因转移已在新生鼠、猫和犬模型中进行了研究，在出生时进行单次肝内注射显示出一定的疗效。AAV8 介导的肝基因转移也在溶酶体贮积症的猫和犬模型中产生了持续的治疗效果。在这些模型中，延迟载体治疗的年龄增加了基因转移的稳定性。婴儿非人灵长类动物的生长速度与人类的生长轨迹更为相似，因此婴儿猴子为研究 AAV 基因转移效率、稳定性和安全性提供了一个极好的模型。在这项研究中，我们首次报告，与青少年动物相比，AAV8 介导的婴儿猴子肝基因转移既安全又有效，但稳定性较差。在出生后 1 周龄时经静脉给予 AAV8 的婴儿猴子在注射后 7 天内达到高达 98%的肝细胞转导；然而，在给药 35 天后，基因组显著稀释，转基因表达丧失。将注射时间推迟到出生后 1 个月不会提高转导的稳定性，但会降低对 AAV8 衣壳的抗体反应。
