Pilot Study of Fingolimod Treatment in Neuronal Ceroid Lipofuscinosis Type 1

Neuronal ceroid lipofuscinosis type 1 (CLN1) is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the PPT1 gene, leading to lipofuscin accumulation, neurodegeneration, psychomotor regression, seizures, and vision loss, with early death in infancy. Currently, no curative treatment exists. Neuroinflammation plays a major role in CLN1 pathophysiology, making anti-inflammatory treatments a potential option. Fingolimod, an immune modulator approved for multiple sclerosis (MS), has shown efficacy in reducing neurodegeneration in CLN1 mouse models. Neurofilament light chain (NfL), a key axonal structural protein, is a biomarker of neuronal damage, with elevated levels indicating axonal injury in various neurologic diseases. We report on 2 pediatric patients with CLN1 treated with fingolimod to assess clinical response and its impact on NfL levels.

This study involved 2 patients with CLN1 who were treated with fingolimod under a compassionate use program at Great Ormond Street Hospital. Inclusion criteria required a molecular diagnosis of CLN1. Patient 1 was monitored over a 36-month period, while patient 2 was followed for 15 months. Fingolimod was administered daily, with dosing adjusted based on age and weight. Lymphocyte counts and NfL levels were regularly measured throughout the study to assess treatment response. The primary outcome was the evaluation of the safety profile following the SOP for fingolimod administration at GOSH. Secondary outcomes included clinical assessments to monitor disease progression and lymphocyte count. As an exploratory outcome, we measured NfL levels, which serve as a biomarker of neuroinflammation and axonal injury.

Two patients with CLN1 were treated with fingolimod under compassionate use. Patient 1 showed a >50% reduction in NfL levels after 14 months, approaching normal results after 2 years, while patient 2 had limited NfL data but generally lower levels, possibly due to later disease onset. No major safety concerns were observed. No clinical improvements were seen, although some stabilization was observed despite expected disease progression.

The significant reduction in NfL levels observed suggests reduced neuroaxonal damage secondary to immune modulation. This finding highlights the potential role of immune modulation in addressing underlying inflammatory processes in CLN1, even if it does not fully halt disease progression.