Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal, rare, autosomal recessive, currently untreatable, childhood neurodegenerative lysosomal storage disease that presents at age 2-4, with cognitive and motor impairment and death by ages 10 to 12. This proposal is a clinical therapeutic study using AAVrh.10CUhCLN2, a non-human primate derived adeno-associated virus serotype rh.10 gene transfer vector, to transfer the CLN2 cDNA, coding for tripeptidyl peptidase I (TPP-I) protein to the brain of children with LINCL. Previous clinical data from this laboratory using a less efficient delivery system (AAV human serotype 2) to the CNS suggested AAV-mediated gene transfer has the potential to slow down the progression of the disease. Pre-clinical data demonstrate that an AAVrh.10- based vector is considerably more effective than AAV2 in animal models, with enhanced performance and survival when administered to the CNS of the CLN2 knockout mice. Administration of this vector to the cortex of non-human primates demonstrated safety and widespread expression of human TPP-I, significantly beyond that achieved with AAV2. Based on this data, we propose a clinical trial for 16 children with LINCL with early disease, with an ascending dose design with the AAVrh.10CUhCLN2 vector compared to a parallel, untreated control group. All study individuals will be monitored before and after vector administration with a variety of safety measures. The primary aims are: (1) to assess the hypothesis that direct administration of AAVrh.10CUhCLN2 to the brain of children with LINCL can be achieved safely with minimal toxicity and to establish the anti-vector and anti-transgene immune response to the therapy;and (2) within the constraint of a study design focused on safety and the ethical considerations regarding a fatal disorder of childhood, to evaluate the hypothesis that direct administration of AAVrh.10CUhCLN2 to the brain of children with LINCL will slow down or halt progression of the disease as assessed by periodic videotaped, multiple observer blinded evaluation of the Weill Cornell LINCL-specific neurologic rating scale and quantitative CNS MRI assessment of % grey matter volume, ventricular volume and cortical apparent diffusion coefficient. The study has Weill Cornell IRB and CTSC approval, approval by the NIH DNA Recombinant Advisory Committee after public review, and the IND is undergoing review at the FDA.

Public Health Relevance

Late infantile neural ceroid lipofuscinosis (LINCL) is a rare, genetic, fatal disorder of childhood characterized by progressive loss of brain function. It is caused by inherited abnormalities in the CLN2 gene, the product of which helps brain cells clear used proteins. This study is designed to assess the safety and efficacy of treating children with LINCL with direct brain administration of the normal CLN2 gene delivered via the rh.10 adeno-associated gene transfer virus. The treated children will be assessed with a number of safety and neuro-specific and clinical and imaging parameters compared to untreated children.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZNS1-SRB-G (44))
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Morris, Jill A
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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