Preclinical development of a gene therapy for Niemann-Pick disease, type A

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DESCRIPTION (provided by applicant): The broad aim of this project is to develop an efficient means to deliver to the human brain a genetic therapy to ameliorate the neurological deficits encountered in Type A Niemann-Pick disease (NPD). Armed with mouse efficacy data, we are confident that an AAV vector that encodes human acidic sphingomyelinase (hASM) is likely to be effective in treating the disease in humans. A major challenge, however, is that widespread expression of hASM will probably be required in order to achieve significant clinical improvement in humans. Efficacy data in knockout mice, although encouraging, does not really address the technical issues that we face in the very much larger human brain. Clinical efficacy will rely considerably upon the development of techniques to deliver gene therapy vectors to such sensitive and highly problematic regions as brainstem. Recently, we have developed a method of visualizing placement of infusion cannulas on MRI, and can actually follow infusion of liposomes tagged with Gadolinium in real-time, termed Real-time Convective Delivery (RCD). In preliminary experiments, we found that these liposomes distribute very like AAV1. We hypothesize that a mixture of AAV1 containing the hASM cDNA and GDL will permit real-time tracking of AAV-mediated gene therapy. We plan to use MRI-guided delivery of AAV1-hASM in the development of a therapy for Niemann-Pick disease. We propose experiments in this application that we believe will form the basis of a major improvement in brain gene therapy in general, and more specifically in the treatment of neurological aspects of LSD's.