PDF(Pubmed)
Abstract：
BACKGROUND: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is a childhood dementia caused by inherited mutations in the sulfamidase gene. At present, there is no treatment and children with classical disease generally die in their late teens. Intravenous or intra-cerebrospinal fluid (CSF) injection of AAV9-gene replacement is being examined in human clinical trials; evaluation of the impact on brain disease is an intense focus; however, MPS IIIA patients also experience profound, progressive photoreceptor loss, leading to night blindness.
OBJECTIVE: To compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice.
METHODS: Neonatal mice received i.v. or intra-CSF AAV9-sulfamidase or vehicle and after 20 weeks, biochemical and histological evaluation of neuroretina integrity was carried out.
RESULTS: Both treatments improved central retinal thickness; however, in peripheral retina, outer nuclear layer thickness and photoreceptor cell length were only significantly improved by i.v. gene replacement. Further, normalization of endo-lysosomal compartment size and microglial morphology was only observed following intravenous gene delivery.
CONCLUSIONS: Confirmatory studies are needed in adult mice; however, these data indicate that i.v. AAV9-sulfamidase infusion leads to superior outcomes in neuroretina, and cerebrospinal fluid-delivered AAV9 may need to be supplemented with another therapeutic approach for optimal patient quality of life.
OBJECTIVE: To compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice.
METHODS: Neonatal mice received i.v. or intra-CSF AAV9-sulfamidase or vehicle and after 20 weeks, biochemical and histological evaluation of neuroretina integrity was carried out.
RESULTS: Both treatments improved central retinal thickness; however, in peripheral retina, outer nuclear layer thickness and photoreceptor cell length were only significantly improved by i.v. gene replacement. Further, normalization of endo-lysosomal compartment size and microglial morphology was only observed following intravenous gene delivery.
CONCLUSIONS: Confirmatory studies are needed in adult mice; however, these data indicate that i.v. AAV9-sulfamidase infusion leads to superior outcomes in neuroretina, and cerebrospinal fluid-delivered AAV9 may need to be supplemented with another therapeutic approach for optimal patient quality of life.
摘要：
背景：Sanfilippo综合征（IIIA型粘多糖贮积症；MPSIIIA）是由磺酰胺酶基因的遗传突变引起的儿童痴呆。目前,没有治疗方法，患有经典疾病的儿童通常在青少年晚期死亡。在人体临床试验中正在检查静脉或脑脊液（CSF）注射AAV9基因替代；对脑部疾病的影响的评估是一个重点；然而，MPSIIIA患者也体会深刻,进行性光感受器丧失,导致夜盲症。
目的：比较两种治疗方法对MPSIIIA小鼠视网膜变性的相对疗效。
方法：新生小鼠接受静脉内或CSF内AAV9-磺酰胺酶或载体，20周后，进行了神经视网膜完整性的生化和组织学评估。
结果：两种治疗方法均可改善视网膜中央厚度；然而，在周边视网膜，外核层厚度和感光细胞长度仅通过i.v.基因置换显着提高。Further,仅在静脉内基因递送后观察到内溶酶体区室大小和小胶质细胞形态的正常化。
结论：需要对成年小鼠进行验证性研究；然而，这些数据表明静脉内输注AAV9-磺酰胺酶导致神经视网膜的优越结局,脑脊液递送的AAV9可能需要补充另一种治疗方法，以获得最佳患者生活质量。
目的：比较两种治疗方法对MPSIIIA小鼠视网膜变性的相对疗效。
方法：新生小鼠接受静脉内或CSF内AAV9-磺酰胺酶或载体，20周后，进行了神经视网膜完整性的生化和组织学评估。
结果：两种治疗方法均可改善视网膜中央厚度；然而，在周边视网膜，外核层厚度和感光细胞长度仅通过i.v.基因置换显着提高。Further,仅在静脉内基因递送后观察到内溶酶体区室大小和小胶质细胞形态的正常化。
结论：需要对成年小鼠进行验证性研究；然而，这些数据表明静脉内输注AAV9-磺酰胺酶导致神经视网膜的优越结局,脑脊液递送的AAV9可能需要补充另一种治疗方法，以获得最佳患者生活质量。
