Perinatal gene therapy for severe genetic diseases

我们研究了使用腺相关病毒（AAV）载体对异染性脑白质营养不良（MLD）和低磷酸酶症（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，检测到基因穿过血脑屏障进入脑内的全局基因转移和无免疫反应的长期基因表达。治疗后神经系统症状明显改善。HPP小鼠胎仔经子宫腹腔注射AAV载体。活产小鼠表现出改善矿化，表型校正和延长生存。这些数据表明，在围产期全身注射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.