Limited therapeutic efficacy of N-acetyl-L-leucine in a mouse model of CLN1 disease.

CLN1 disease, one of the most severe forms of neuronal ceroid lipofuscinosis (NCLs or Batten disease), is a rapidly progressing pediatric neurodegenerative disorder caused by mutations in the PPT1 gene. The disease is characterized by lysosomal storage accumulation, an early onset neuroimmune response, motor impairment, and premature death. N-acetyl-L-leucine (NALL), an orally bioavailable modified amino acid, has demonstrated clinical efficacy in Niemann–Pick type C and other lysosomal storage disorders. Here, we assessed the efficacy of chronic NALL treatment in the Ppt1−/− mouse model of CLN1 disease. Mice received NALL (0.1 g/kg/day) in chow either from weaning (1 month, presymptomatic) or from 4 months (symptomatic) until 7 months (normal disease endstage), with additional survival cohorts. NALL treatment did not extend survival in Ppt1−/− mice and produced no significant improvement in gait coordination or rotarod performance, with only minimal improvements in select gait variability parameters in presymptomatically treated mice. Histological analyses revealed no reduction in microglial or astrocyte activation, nor in storage material accumulation, key CLN1 disease-associated phenotypes. These findings indicate that NALL monotherapy has limited therapeutic efficacy in CLN1 disease mice and suggest that its mechanisms of action may not address the underlying pathophysiology of this disorder.