Research ArticleGene Therapy

Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2

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Science Translational Medicine  02 Dec 2020:
Vol. 12, Issue 572, eabb5413
DOI: 10.1126/scitranslmed.abb5413

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Gene therapy for CLN2 disease

The current treatment for CLN2 disease, caused by mutations in the CLN2 gene, is infusion of human recombinant tripeptidyl peptidase 1 (TPP1) into the cerebrospinal fluid every other week, which slows but does not halt progression of the disease. Sondhi and colleagues sought an alternative treatment through gene therapy. They injected an adeno-associated virus vector expressing the normal human CLN2 coding sequence directly into the brain parenchyma of children with the disease. Progression of the disease was slowed in treated children but not to the same degree as recombinant TPP1. Further improvements in gene therapy are needed before progression of CLN2 disease can be halted.


Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human CLN2, 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 (P < 0.04) and European natural history cohort (P < 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.

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