Intra-arterial Gene Therapy for LINCL

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 DESCRIPTION (provided by applicant): The overall goal of this project is to develop a new strategy for treatment and evaluation of a uniformly fatal pediatric neurodegenerative disease known as Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL), which is a form of Batten disease. Specifically, we will examine the value of intra-arterial (IA) delivery of viral vector mediated gene therapy in a preclinical model of LINCL, and develop imaging techniques to assess disease severity, vector distribution, and therapeutic efficacy. At present no therapy for LINCL has been shown to yield significant survival or quality of life benefits in humans, highlighting the critical need for the development of new therapeutic strategies. LINCL is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations of the CLN2 gene. A defect in this gene results in a lack of tripeptidyl peptidase-1 (TPP-I), and a resultant accumulation of autofluorescent material resembling lipofuscin in lysosomes, with widespread progressive neurodegeneration and death occurring by the ages of 10-12 years. One treatment for LINCL that has shown promise in both animal and clinical studies is gene therapy using adeno-associated viral vectors (AAV). However, currently this therapy is administered to the brain by direct infusion, a procedure that requires major surgery. Instead, we propose to develop IA injection techniques whereby therapy is delivered through an endovascular catheter directly to the arteries that supply blood to the disease afflicted tissue. We will address three Specific Aims: Specific Aim 1: Express the CLN2 gene in the mouse brain using intra-arterial delivery of two serotypes of AAV, namely AAVrh.10CLN2 and AAV9CLN2. Intra-arterial and intravenous delivery will be compared to our earlier studies using direct infusion. Specific Aim 2: Develop non-invasive tools for measuring LINCL disease severity, viral vector delivery, and therapeutic response. We will develop a multi-component magnetic resonance imaging biomarker panel to measure LINCL severity, and use a novel strategy involving positron emission tomography to evaluate vector distribution in the brain. Specific Aim 3: Arrest LINCL disease progression in CLN2-/- mice using intra-arterial delivery of AAVrh.10CLN2 or AAV9CLN2. A survival study will be conducted and mice will be evaluated using imaging, behavioral, and histological methods. If we are successful, this work would lead to a clinical trial in human subjects. Also, we would advance the field of intra-arterial drug delivery by standardizing administration parameters in genetically engineered mice for successful IA delivery of gene therapy to the central nervous system. Finally, many of the results from this project, including those from both gene delivery and imaging, will not be specific to LINCL but will be applicable to a wide range of neurological and other disorders.