Cellular Mechanisms of Enteric Nervous System Damage in CLN2 Disease

Project Summary/Abstract: The neuronal ceroid lipofuscinosis (NCL or Batten disease), are a group of rare neurodegenerative lysosomal storage disorders (LSDs). Through mechanisms that remain poorly understood, inherited mutations that cause lysosomal dysfunction in the NCLs result in profound neurodegeneration within the central nervous system (CNS). Although progress has been made recently to produce disease-modifying treatments, none of these CNS-directed therapies are completely effective. We hypothesized that one reason CNS-directed therapies are incompletely effective is that lysosomal dysfunction also results in loss of neurons outside the CNS, specifically within the enteric nervous system (ENS). The ENS is the intrinsic nervous system of the bowel and controls most aspects of bowel function, with ENS defects causing life-threatening disease. These underappreciated effects of lysosomal dysfunction upon the bowel are unlikely to be treated effectively by CNS-directed therapies. Our preliminary data reveal profound ENS neurodegeneration in mouse models of CLN1, CLN2 and CLN3 disease, the major forms of NCL. These mice have bowel transit defects, that can be partly treated by neonatal delivery of intravenous gene therapy using adeno-associated viral vectors (AAV9). However, optimal therapy will require a better understanding of which bowel cell types are affected by lysosomal dysfunction and the cellular mechanisms underlying ENS neurodegeneration. Since our data show CNS-directed therapies do not treat the bowel, and bowel-directed therapies do not effectively treat the CNS, we will also test the hypothesis that optimal outcomes will require combined CNS- and ENS-directed therapy. For logistical reasons we shall explore these issues in a mouse model of CLN2 disease, which has rapidly progressing and severe enteric neurodegeneration and dies at an earlier age than mice with other major forms of NCL. In Aim 1 we shall define how different bowel cell types are affected by CLN2 deficiency, identifying cellular targets for gene therapy or that may be druggable. In Aim 2 we shall use novel transgenic mice to address which cell types critically need treating to preserve ENS function. In Aim 3 we will test combined approaches to simultaneously treat bowel and brain to define those most suited for subsequent clinical trials. Taken together these studies will provide important information for devising targeted therapeutic strategies to treat the effects of disease in the bowel and brain.