Choroid plexus-mediated gene therapy for lysosomal storage disorders

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Choroid plexus-directed gene therapy for lysosomal storage diseases. The choroid plexuses are highly vascularized structures that project into the ventricles of the brain. Besides creating the blood-CSF barrier, the polarized epithelia of the choroid plexus produce CSF by transporting water and ions into the ventricles from the blood and secreting a large number of proteins. A number of neurometabolic diseases, such as lysosomal storage disorders, could benefit from a choroid plexus-targeted gene therapy approach, since CSF flow carries molecules throughout the ventricular system into the subarachnoid space, which covers the entire brain surface.In collaboration with extramural investigators (P. Dickson, UCLA and J. Wolfe, UPenn), we embarked on investigations of choroid plexus-directed gene therapy for mucopolysaccharidosis type IIIB (Sanfilippo B syndrome), a devastating neurological disorder caused by N-acetylglucosaminidase (NAGLU) deficiency, and alpha-mannosidosis, a rare condition characterized by deficiency of the enzyme lysosomal acid alpha-mannosidase and caused by mutations of the LAMAN gene. Intrathecal delivery of recombinant enzyme (injecting enzyme into the cerebrospinal fluid during a spinal tap) has been successful in animal models and some clinical trials of lysosomal storage diseases. However, a major drawback to this approach is the need for repeated (e.g., monthly) intrathecal injections. An alternative route of administration without need for repeated enzyme injections would be transduction of choroid plexus epithelial cells with an AAV vector containing the cDNA for the enzyme of interest. Recombinant AAV transduction results in sustained episomal transgene expression, and CSF flow carries molecules throughout the ventricular system into the subarachnoid space from which molecules ultimately reach the entire brain. We are studying the efficacy of two known AAV serotypes (AAV5 and AAV4), as well as the novel choroid plexus-specific AAV capsid under development (see #1 above). These collaborative studies have supported by external grants from the National MPS Society, and the NIH Bench-to-Bedside and U01 programs.