JNCL is a devastating childhood-onset neurodegenerative disease caused by deficiency in CLN3, a membrane-integral protein with unresolved function. Using a Cln3-reporter mouse, we previously discovered that in the postnatal mouse brain, expression is limited to a few subpopulations of neurons, but is widespread in endothelial cells (EC) that line the vasculature. Our continued studies show that brain EC from CLN3-deficient mice display impairments in drug efflux, regulatory volume response, and endocytosis. These functions are critical to normal operation of the blood-brain barrier (BBB), which governs selective passage of molecules between blood and brain, mediating import of nutrients and export of toxic substances away from proximal neurons. We postulate that brain EC dysfunction plays a dominant role in JNCL pathogenesis, and that restoring CLN3 to EC will alleviate disease progression. The current proposal seeks to test our hypothesis via two main Aims.
For Aim 1 we plan to use a transgenic mouse approach to trigger EC-exclusive expression of CLN3, and assess whether this prevents the development of behavioral 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 JNCL mouse model. Accomplishment of these aims will provide valuable information relevant to JNCL pathogenesis and potential treatment avenues. Should our hypothesis prove correct, this would distinguish central nervous system EC as a therapeutic target for JNCL. Moreover, therapeutic efficacy of our gene transfer approach, in which the vector is administered via intra-vascular injection, would be an exciting outcome with hope for translation to JNCL patients, and possibly more broadly to other neurodegenerative diseases.

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Morris, Jill A
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Children's Hospital of Philadelphia
United States
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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