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Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice.
Life Science Alliance ( IF 4.4 ) Pub Date : 2021-08-18 , DOI: 10.26508/lsa.202101040
Cristin D Davidson 1 , Alana L Gibson 1 , Tansy Gu 1 , Laura L Baxter 1 , Benjamin E Deverman 2 , Keith Beadle 2 , Arturo A Incao 1 , Jorge L Rodriguez-Gil 1 , Hideji Fujiwara 3 , Xuntian Jiang 3 , Randy J Chandler 4 , Daniel S Ory 3 , Viviana Gradinaru 2 , Charles P Venditti 5 , William J Pavan 6
Affiliation  

Niemann-Pick C1 disease (NPC1) is a rare, fatal neurodegenerative disease caused by mutations in NPC1, which encodes the lysosomal cholesterol transport protein NPC1. Disease pathology involves lysosomal accumulation of cholesterol and lipids, leading to neurological and visceral complications. Targeting the central nervous system (CNS) from systemic circulation complicates treatment of neurological diseases with gene transfer techniques. Selected and engineered capsids, for example, adeno-associated virus (AAV)-PHP.B facilitate peripheral-to-CNS transfer and hence greater CNS transduction than parental predecessors. We report that systemic delivery to Npc1 m1N/m1N mice using an AAV-PHP.B vector ubiquitously expressing NPC1 led to greater disease amelioration than an otherwise identical AAV9 vector. In addition, viral copy number and biodistribution of GFP-expressing reporters showed that AAV-PHP.B achieved more efficient, albeit variable, CNS transduction than AAV9 in Npc1 m1N/m1N mice. This variability was associated with segregation of two alleles of the putative AAV-PHP.B receptor Ly6a in Npc1 m1N/m1N mice. Our data suggest that robust improvements in NPC1 disease phenotypes occur even with modest CNS transduction and that improved neurotrophic capsids have the potential for superior NPC1 AAV gene therapy vectors.

中文翻译:

在 Niemann-Pick 病 C1 型小鼠中使用神经营养衣壳改进了系统性 AAV 基因治疗。

Niemann-Pick C1 病 (NPC1) 是一种罕见的致命神经退行性疾病,由编码溶酶体胆固醇转运蛋白 NPC1的NPC1突变引起。疾病病理学涉及胆固醇和脂质的溶酶体积累,导致神经和内脏并发症。从体循环靶向中枢神经系统 (CNS) 使使用基因转移技术治疗神经系统疾病变得复杂。选择和工程化的衣壳,例如腺相关病毒 (AAV)-PHP.B 促进外周到中枢神经系统的转移,因此比亲本前身有更大的中枢神经系统转导。我们报告使用普遍表达NPC1的 AAV-PHP.B 载体向Npc1 m1N/m1N小鼠全身递送导致比其他方面相同的 AAV9 载体更大的疾病改善。此外,表达 GFP 的报告基因的病毒拷贝数和生物分布表明,AAV-PHP.B 在Npc1 m1N/m1N小鼠中实现了比 AAV9 更有效的中枢神经系统转导,尽管是可变的。这种变异性与Npc1 m1N/m1N小鼠中推定的 AAV-PHP.B 受体Ly6a的两个等位基因的分离有关。我们的数据表明,即使在适度的中枢神经系统转导下,NPC1 疾病表型的显着改善也会发生,并且改进的神经营养衣壳具有优越的 NPC1 AAV 基因治疗载体的潜力。
更新日期:2021-08-18
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