Perinatal gene therapy for severe genetic diseases

我们探讨了用腺相关病毒(AAV)载体对异染性白质营养不良(MLD)和低磷酸盐血症(HPP)模型小鼠进行产前/新生儿基因治疗的可行性。将AAV载体静脉注射到新生MLD小鼠体内后，可检测到跨血脑屏障的全局性基因转移和无免疫反应的长期基因表达。治疗后神经症状明显改善。HPP小鼠胚胎经腹膜腔内注射AAV载体。活着出生的小鼠表现出矿化改善、表型纠正和延长存活时间。这些数据表明，围产期系统注射AAV载体是治疗MLD和HPP等严重遗传性疾病的有效策略。

We investigated the feasibility of prenatal/neonatal gene therapy of both metachromatic leukodystrophy (MLD) and hypophosphatasia (HPP) model mice using adeno-associated viral (AAV) vectors. After intravenous injection of AAV vector into neonatal MLD mice, global gene transfer into the brain across the BBB and long term gene expression without immune reaction were detected. Significant improvement of neurological symptoms was observed after treatment. The fetuses of HPP mice underwent transuterine intraperitoneal injection of AAV vector. Live-born mice showed improved mineralization, phenotypic correction and prolonged survival. These data demonstrated that systemic injection of AAV vector in the perinatal period is an effective strategy for the treatment of severe genetic diseases such as MLD and HPP.