Bowel dysmotility and enteric neuron degeneration in lysosomal storage disease mice is prevented by gene therapy

Background and aimsChildren with neurodegenerative disease often have debilitating gastrointestinal (GI) symptoms that may be due at least in part to underappreciated involvement of neurons in the enteric nervous system (ENS), the master regulator of bowel function. MethodsWe investigated bowel motility in mouse models of CLN1 and CLN2 disease, neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 (PPT1) and tripeptidyl peptidase-1 (TPP1), respectively. We then explored the integrity of ENS anatomy in immunostained bowel wholemount preparations from these mice. Lastly, we administered adeno-associated viral gene therapy to neonatal mice and determined if this would prevent these newly identified bowel phenotypes. ResultsMouse models of CLN1 and CLN2 disease both displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Neonatal administration of adeno-associated virus-mediated gene therapy prevented bowel transit defects and the loss of many ENS neurons. ConclusionsWe show that two neurodegenerative lysosomal storage diseases cause profound and progressive damage to the mouse enteric nervous system and impair bowel motility. We also provide proof-of-principle evidence that gene therapy can prevent enteric nervous system disease. This study may have general therapeutic implications for many inherited neurodegenerative disorders. What you need to knowO_ST_ABSBackground and ContextC_ST_ABSMany pediatric central nervous system disorders also have debilitating gastrointestinal symptoms. For most of these diseases, it is not known if the enteric nervous system (ENS) is also affected and to what degree ENS defects contribute to GI symptoms. To date, no attempts have been made to directly treat or prevent enteric nervous system disease via gene therapy. New FindingsThe enteric nervous system is severely affected in mouse models of CLN1 and CLN2 disease, profoundly neurodegenerative lysosomal storage disorders. Bowel transit defects and most of the enteric nervous system pathology can be prevented by neonatal administration of gene therapy. LimitationsInformation about enteric nervous system disease in human children is still lacking, and methods will need to be developed to treat the human bowel. ImpactThese findings identify an underappreciated effect of neurodegenerative disease upon the bowel and demonstrate that enteric nervous system degeneration can be prevented in mice. This provides a new perspective on these childhood disorders that may be applicable to many other conditions that affect the bowel. Lay SummaryIn childrens diseases where the brain degenerates, nerve cells in the bowel also die causing gastrointestinal problems, but this can be prevented by gene therapy.