Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of disorders that is collectively the most common cause of childhood onset neurodegeneration in the U.S. and worldwide. Juvenile NCL, which is estimated to affect approximately 1 in 100,000 live births, is caused by recessive CLN3 mutation (hence also now referred to as CLN3 disease). Affected children suffer from progressive blindness, seizures, psychosis, and cognitive and motor failure, and the disease is invariably fatal. CLN3 encodes a novel transmembrane protein (CLN3, or battenin) that localizes to the endocytic pathway, primarily in endolysosomes. The CLN3 protein is implicated in various cellular processes, but the primary function remains incompletely resolved. Given the lack of incomplete knowledge surrounding protein function, limited therapeutic targets have been identified, and the only therapeutic approaches that have moved into clinical testing target secondary inflammation or introduce non-mutated CLN3 via gene transfer therapy. Alternative rational therapeutic targets are badly needed. The research planned in this proposal is focused on identifying modifiers of CLN3 disease, which has high potential to lead to new targets for therapeutic development. We will test a candidate disease modifier that is suggested by CLN3 functional studies, and we will perform unbiased studies utilizing mouse and human cell-based models. In the first aim, we will build from recent progress on discovery of an early-stage lysosomal Ca2+ defect, testing whether activation of the endolysosomal Ca2+ channel, TRPML1, significantly modifies CLN3 disease in mice and in human CLN3 patient cells. These studies will establish key proof-of-concept data, with high potential to lead to a novel treatment for CLN3 disease, also establishing important insight regarding the mechanisms linking CLN3 to TRPML1. Studies to be carried out in a second aim will build upon the discovery that features of CLN3 disease have a different rate of progression in different genetic mouse strains. Using genetic approaches, we will test the hypothesis that a mutation carried in the mitochondrial DNA of FVB/N mice leads to a more rapid disease, and we will perform further studies to define the role of mitochondrial quality control in CLN3 disease. The candidate gene modifiers from these studies will also be tested in CLN3 patient derived iPSC models. This research to identify and validate CLN3 disease modifying factors has high potential to ultimately lead to novel treatments that would have a meaningful impact on CLN3 disease in the future.
CLN3 disease is a rare Mendelian disorder with an estimated incidence of ~1 in 100,000 live births, and is one of a group of disorders collectively known as neuronal ceroid lipofuscinosis (NCL, or Batten disease), which also share genetic and pathologic overlap with other neurological diseases including frontotemporal lobar degeneration and Parkinson disease. CLN3 disease is caused by mutations in CLN3, encoding a transmembrane protein of unknown function localized to endolysosomes. There are no treatments to prevent, slow or reverse CLN3 disease, which is invariably fatal, and therefore, more research is urgently needed to identify, and ultimately clinically develop, disease-modifying treatments.
