Enteric nervous system degeneration in human and murine CLN3 disease, is ameliorated by gene therapy in mice

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Neuronal Ceroid Lipofuscinosis (CLN3) disease is known for severe central nervous system (CNS) deficits.
• Peripheral neuromuscular and gastrointestinal problems are less recognized but significant in CLN3 disease.

Purpose of the Study:

• To investigate the impact of CLN3 deficiency on peripheral neuronal and glial cells.
• To examine the neuromuscular and enteric nervous systems in CLN3-deficient mice and human samples.

Main Methods:

• Analysis of neuromuscular junctions (NMJs) and enteric nervous system in Cln3 mice.
• Histopathological examination of muscle biopsies and autopsy tissues from human CLN3 cases.
• Assessment of gene therapy efficacy using an AAV9-hCLN3 vector in Cln3 mice.

Main Results:

• Cln3 mice exhibited loss of terminal Schwann cells, NMJ denervation, myofiber atrophy, and smooth muscle atrophy.
• Significant loss of enteric neurons and glial cells was observed, leading to slow bowel transit.
• Human CLN3 samples showed similar peripheral neuromuscular and enteric pathologies.
• Gene therapy in Cln3 mice prevented NMJ pathology, muscle atrophy, and enteric nervous system degeneration, improving bowel function.

Conclusions:

• CLN3 disease has a substantial, underappreciated impact on peripheral systems beyond the CNS.
• Peripheral neuromuscular and gastrointestinal pathologies in CLN3 disease are potentially treatable with gene therapy.