Research ArticleGene Therapy

AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease

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Science Translational Medicine  11 Nov 2015:
Vol. 7, Issue 313, pp. 313ra180
DOI: 10.1126/scitranslmed.aac6191

Gene therapy for Batten disease

Repeated enzyme replacement therapy via infusion of the enzyme into blood vessels is an established treatment modality for many lysosomal storage diseases but not for those with significant brain involvement. In new work, Katz and colleagues test gene delivery of the missing enzyme to cells that line the fluid-filled spaces of the brain and measure secretion of the enzyme into the cerebrospinal fluid. Using a dog model of a lysosomal storage disease, they show that this strategy delayed disease onset, extended life span, and protected dogs from early cognitive decline, suggesting that this approach could improve the lives of children suffering from the same or similar diseases.


The most common form of the childhood neurodegenerative disease late infantile neuronal ceroid lipofuscinosis (also called Batten disease) is caused by deficiency of the soluble lysosomal enzyme tripeptidyl peptidase 1 (TPP1) resulting from mutations in the TPP1 gene. We tested whether TPP1 gene transfer to the ependyma, the epithelial lining of the brain ventricular system, in TPP1-deficient dogs would be therapeutically beneficial. A one-time administration of recombinant adeno-associated virus (rAAV) expressing canine TPP1 (rAAV.caTPP1) resulted in high expression of TPP1 predominantly in ependymal cells and secretion of the enzyme into the cerebrospinal fluid leading to clinical benefit. Diseased dogs treated with rAAV.caTPP1 showed delays in onset of clinical signs and disease progression, protection from cognitive decline, and extension of life span. By immunostaining and enzyme assay, recombinant protein was evident throughout the brain and spinal cord, with correction of the neuropathology characteristic of the disease. This study in a naturally occurring canine model of TPP1 deficiency highlights the utility of AAV transduction of ventricular lining cells to accomplish stable secretion of recombinant protein for broad distribution in the central nervous system and therapeutic benefit.

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