JNCL is a devastating childhood-onset neurodegenerative disease caused by deficiency in CLN3, amembrane-integral protein with unresolved function. Using a Cln3-reporter mouse, we previouslydiscovered that in the postnatal mouse brain, expression is limited to a few subpopulations of neurons, butis widespread in endothelial cells (EC) that line the vasculature. Our continued studies show that brain ECfrom CLN3-deficient mice display impairments in drug efflux, regulatory volume response, andendocytosis. These functions are critical to normal operation of the blood-brain barrier (BBB), whichgoverns selective passage of molecules between blood and brain, mediating import of nutrients and exportof toxic substances away from proximal neurons. We postulate that brain EC dysfunction plays a dominantrole in JNCL pathogenesis, and that restoring CLN3 to EC will alleviate disease progression. The currentproposal seeks to test our hypothesis via two main Aims.
For Aim 1 we plan to use a transgenic mouseapproach to trigger EC-exclusive expression of CLN3, and assess whether this prevents the development ofbehavioral and pathological measures of JNCL.
In Aim 2, we plan to generate an adeno-associated virus(AAV) vector with tropism for brain endothelium to test the efficacy of CLN3 gene transfer in the JNCLmouse model. Accomplishment of these aims will provide valuable information relevant to JNCLpathogenesis and potential treatment avenues. Should our hypothesis prove correct, this would distinguishcentral nervous system EC as a therapeutic target for JNCL. Moreover, therapeutic efficacy of our genetransfer approach, in which the vector is administered via intra-vascular injection, would be an excitingoutcome with hope for translation to JNCL patients, and possibly more broadly to other neurodegenerativediseases.

Public Health Relevance

The juvenile form of Batten disease (JNCL) is caused by deficiency in CLN3; and results in progressive loss of neurons in the brain and retina; leading to blindness and deterioration of motor and cognitive skills. Our studies indicate that CLN3 is important in endothelial cells that line the blood vessels of the nervous system; and we propose to test whether restoration of CLN3 to these cells prevents JNCL disease in a mouse model. If successful; our strategy of CLN3 gene transfer to endothelial cells could be translated into an effective therapy for human patients; and would allow doctors to treat JNCL and perhaps other neurodegenerative diseases by administering the gene transfer vector intravenously; a route that is much more desirable than direct brain injections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21NS084424-02
Application #
8840690
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Morris, Jill A
Project Start
2013-09-01
Project End
2015-08-31
Budget Start
2014-04-01
Budget End
2014-08-31
Support Year
Fiscal Year
2014
Total Cost
$82,000
Indirect Cost
$33,190
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Schultz, Mark L; Tecedor, Luis; Stein, Colleen S et al. (2014) CLN3 deficient cells display defects in the ARF1-Cdc42 pathway and actin-dependent events. PLoS One 9:e96647