Abstract
CLN diseases are rare lysosomal storage diseases characterized by progressive axonal degeneration and neuron loss in the CNS, manifesting in disability, blindness, and premature death. We have previously demonstrated that, in animal models of infantile and juvenile forms of CLN disease (CLN1 and CLN3, respectively), secondary neuroinflammation in the CNS substantially amplifies neural damage, opening the possibility that immunomodulatory treatment might improve disease outcome. First, we recapitulated the inflammatory phenotype, originally seen in mice in autopsies of CLN patients. We then treated mouse models of CLN1 and CLN3 disease with the clinically approved immunomodulatory compounds fingolimod (0.5 mg/kg/day) and teriflunomide (10 mg/kg/day) by consistent supply in the drinking water for 5 months. The treatment was well tolerated and reduced T cell numbers and microgliosis in the CNS of both models. Moreover, axonal damage, neuron loss, retinal thinning, and brain atrophy were substantially attenuated in both models, along with reduced frequency of myoclonic jerks in Ppt1-/- mice. Based on these findings, and because side effects were not detected, we suggest that clinically approved immune modulators such as fingolimod and teriflunomide may be suitable to attenuate progression of CLN1 and CLN3 disease and, possibly, other orphan diseases with pathogenically relevant neuroinflammation.