Late Infantile Neuronal Ceroid Lipofuscinosis (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 I, and a resultant accumulation of autofluorescent material resembling lipofuscin in lysosomes. Neurons are particularly sensitive to this accumulation and children with this disease exhibit widespread progressive neurodegeneration with death occurring around the ages of 10-12 years. One treatment that has shown promise in both animal and clinical studies is gene therapy. However, since this therapy cannot pass from the blood stream to the brain because of the blood brain barrier (BBB), this treatment has been administered to the central nervous system by directly infusing a solution containing the therapy into brain tissue, a procedure that requires multiple craniotomies and major surgery. This project aims to assess the ability of intra-arterial (IA) injection in conjunction with osmolar BBB disruption to treat a preclinical model of LINCL with gene therapy. In IA injection the therapy is delivered through an endovascular catheter directly to the arteries that supply blood to the disease afflicted tissue and as a result this technique can achieve very high drug tissue concentrations with reduced systemic exposure. To assess the effectiveness of this delivery route for treatment of LINCL with gene therapy we will examine these specific aims: 1) Demonstrate intra-arterial injection and blood brain barrier disruption in the mouse brain We will inject a paramagnetic contrast agent in the cervical internal carotid artery (ICA) of mice with and without BBB disruption, and monitor the distribution of the injection with real-time magnetic resonance imaging (MRI). 2) Transfect mouse brain cells with CLN2 gene using intra-arterial delivery of adeno-associated viral vector We will use the techniques and parameters developed in specific aim 1 to perform IA delivery of a viral-vector encoding the CLN2 gene to the brains of mice. We will examine different concentrations of vector to determine the dose that gives the best neural transfection while minimizing systemic exposure. 3) Use IA delivery of CLN2 gene therapy to arrest LINCL progression in CLN2-/- mice. Our final specific aim will use the results of specific aims 1 and 2 to perform IA delivery of the CLN2 gene to a knockout CLN2-/- mouse model of LINCL. The effect of gene therapy on disease progression will be assessed using non-invasive MRI examination.

Public Health Relevance

The goal of this project is to determine if intra-arterial injection of gene therapy can effectively treat neurological disorders. This technique may provide a safer and less invasive route for delivering drugs to neural tissue, and could be of use in a host of clinical neurological diseases such as cancer, Alzheimer's disease, Batten disease, Parkinson's disease, and stroke. The results of this project will help to establish techniques and conditions that will enable efficient pre-clinical testing of intra-arterial delivery of promising therapies for neurological diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F15-D (20))
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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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