CLN1 disease or Infantile Neuronal Ceroid Lipofuscinosis (INCL or Infantile Batten disease) is one of the earliest onset and most rapidly progressing forms of neuronal ceroid lipofuscinosis (NCL or Batten disease). CLN1 disease is caused by deficiency in the lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1), and has a devastating impact upon the central nervous system (CNS). Symptoms start within the first year of life and progress rapidly, and because there is no effective therapy, CLN1 disease is always fatal. While the catastrophic effects of PPT1 deficiency upon the CNS are well appreciated, relatively little is formally known about disease phenotypes outside the brain and spinal cord. Nonetheless, physicians and parents of affected children consistently report severe gastrointestinal (GI) problems that dramatically reduce quality of life for affected children and their families. These include abdominal pain, bloating, severe constipation and impaired bowel motility. These GI problems were previously attributed to CNS disease or medicine side effects, but our preliminary data provide a novel alternative cause that is amenable to treatment. These new preliminary data show pronounced pathological and functional effects of CLN1 disease in the enteric nervous system (ENS) of PPT1-deficient mice. Now we will more thoroughly characterize this ENS neurodegenerative phenotype in PPT1 deficient mice, and quantify effects on bowel motility as CLN1 disease mice age. In parallel, we will determine how systemic AAV-mediated gene therapy impacts ENS pathology and bowel function. We have already demonstrated that neonatal CNS delivery of an AAV2/9 vector expressing PPT1 remarkably improves brain and spinal cord function in CLN1 disease mice. The same AAV2/9 vectors also efficiently transduce the ENS when injected intravenously in young mice. Therefore, we will determine if simultaneously rescuing PPT1 function in CNS and ENS leads to a more robust therapeutic response compared to CNS treatment alone. We will achieve these goals with the following specific aims.
Specific Aim 1 : To determine the extent and nature of enteric nervous system damage and evaluate bowel motility in Cln1 disease mice.
Specific Aim 2 : To treat enteric nervous system disease with AAV-mediated gene therapy. Our preliminary data suggest that many the gastrointestinal manifestations of CLN1 disease that negatively impact the life quality of affected children may occur because of unexpected and underappreciated damage to the ENS. We will define the nature and progression of ENS pathology, and how it affects bowel function, before testing the efficacy of AAV-mediated gene therapy to prevent these debilitating, but poorly recognized gastrointestinal effects of CLN1 disease.
Our goal is to find new ways to treat CLN1 disease or Infantile Neuronal Ceroid Lipofuscinosis (or Infantile Batten disease), a fatal untreatable neurodegenerative disorder of childhood. Our new preliminary data suggest that many of the severe gastrointestinal manifestations of CLN1 disease may occur because of damage to the enteric nervous system (ENS). We will first define the onset and progression of ENS degeneration in Cln1 disease mice and the impact upon bowel function, before testing if these phenotypes can be treated via gene therapy.
