Sondhi Dolan, Kaminsky Stephen M, Hackett Neil R, Pagovich Odelya E, Rosenberg Jonathan B, De Bishnu P, Chen Alvin, Van de Graaf Benjamin, Mezey Jason G, Mammen Grace W, Mancenido Denesy, Xu Fang, Kosofsky Barry, Yohay Kaleb, Worgall Stefan, Kaner Robert J, Souwedaine Mark, Greenwald Bruce M, Kaplitt Michael, Dyke Jonathan P, Ballon Douglas J, Heier Linda A, Kiss Szilard, Crystal Ronald G
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.
Sci Transl Med. 2020 Dec 2;12(572). doi: 10.1126/scitranslmed.abb5413.
Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human , in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort ( < 0.04) and European natural history cohort ( < 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy.
晚发性婴儿型巴滕病（CLN2病）是一种常染色体隐性神经退行性溶酶体贮积病，由编码三肽基肽酶1（TPP1）的基因突变引起。在一项非随机试验中，我们测试了AAVrh.10hCLN2（一种编码人TPP1的非人血清型rh.10腺相关病毒载体）的脑实质内递送。该试验由两个组构成，评估期为18个月：8名轻度至中度疾病儿童的AAVrh.10hCLN2治疗组，以及12名儿童组成的未治疗的威尔康奈尔自然史队列组。治疗组还与一个未治疗的欧洲CLN2病自然史队列组进行了比较。该载体通过六个钻孔直接注射到大脑的12个部位，无需免疫抑制。在另一项单独方案下的安全性评估中，5名重度CLN2病儿童接受了AAVrh.10hCLN2治疗。该疗法伴有多种预期不良事件，但均未导致长期残疾。全身性抗AAVrh.10免疫的诱导较为轻微。治疗后，治疗组脑脊液中的TPP1增加了1.3至2.6倍。与威尔康奈尔自然史队列组（P<0.04）和欧洲自然史队列组（P<0.0001）相比，通过磁共振成像（MRI）检查发现，7名儿童中有4名灰质体积减少速度减慢，运动和语言功能衰退率分别降低了42.4%和47.5%。脑实质内注射AAVrh.1hCLN2可减缓CLN2病儿童的疾病进展。然而，若要通过基因疗法阻止疾病进展，仍需改进载体设计和递送策略。
