Local Research

A novel injectable treatment for a deadly neurodegenerative disease, juvenile NCL or CLN3 disease is being tried in a mouse model: GalactosylCeramide in CLN3-deficient mice (Batten Disease)

Sally El-Sitt (PhD student), Jihanne Souied PhD, Joelle Makoukji, PhD and Rose-Mary Boustany.


Juvenile Neuronal Ceroid Lipofuscinosis (JNCL or CLN3 disease), a disease that affects children, leads to visual failure followed by seizures, motor decline and death at the ages of 20-30.  It is the most prevalent among the Neuronal Ceroid Lipofuscinoses (NCLs). Pathological hallmarks include accelerated brain cell death and accumulation of autofluorescent material (mainly subunit c) in neurons in the brain and organs. The ∼1 kb gene deletion eliminating exons 7/8 of the CLN3 gene is the most common human mutation responsible. CLN3 encodes a protein (CLN3p), and, important roles of CLN3p are: hat it is protective against cell death or is antiapoptotic, it facilitates transport of galactosylceramide (GalCer), a crucial sphingolipid component of lipid rafts in plasma membrane from Golgi to lipid rafts. Mutated CLN3p results in disrupted transport of GalCer with retention in Golgi and recycling endosomes without localization to lipid rafts. To compensate, an increase in ceramide levels follows, aggravating apoptosis and resulting in massive neuronal loss. Data from our laboratory has shown that GalCer added to CLN3-deficient cells corrected the deficit in LRs, diminished apoptosis and ceramide levels. This increase in ceramide has been documented in brains of patients and a mouse model and serum from patients. The Cln3Δex7/8   knock-in mouse model manifests human biochemical, pathologic and behavioral changes and, is a good model to test therapeutic strategies. Preliminary injection of GalCer in the Cln3Δex7/8 mouse from 8-17 weeks reduced subunit c accumulation in brain, liver and kidneys, and lowered brain ceramide in mice. Moreover, GalCer improved locomotor activity in affected mice. An expanded mouse clinical trial with treatment over a longer period of time, and including a larger number of GalCer vs. placebo treated mice is underway to assess the impact of prolonged GalCer treatment on different aspects of the disease. This will be accomplished by assessing ceramide levels before and after the injections in serum and brain, staining for subunit C, examining microglial activation and gliosis, apoptotic indeces, in addition to determining the impact of GalCer administration on motor function and exploratory behavior of Cln3Δex7/8 mice. The latter is being accomplished with a battery of behavioral tests (wire hanging, grip strength meter measures, pole climbing, rotarod and T-maze performance). Data is being collected from male and female affected and unaffected mice, GalCer and placebo treated affected mice. It is hoped that GalCer injections will lead to Improvement in the neuropathology of GalCer treated mice with a decrease in brain cell death and an enhanced behavioral outcome.  This will lay the groundwork for future clinical trials in affected children.