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Neurofilament light is a treatment-responsive biomarker in CLN2 disease
Yuanbin Ru1, Carley Corado2, Russell K Soon3
1Research, BioMarin Pharmaceutical Inc., Novato, California, 94949.
Objective:
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare, progressive, fatal neurodegenerative pediatric disorder resulting from deficiencies of the lysosomal enzyme tripeptidyl peptidase 1 that are caused by mutations in TPP1. Identifying biomarkers of CLN2 disease progression will be important in assessing the efficacy of therapeutic interventions for this disorder. Neurofilament light is an intrinsic component of healthy neurons; elevated circulating extracellular neurofilament light is a biomarker of neuropathology in several adult-onset neurological diseases. Our objective was to assess whether circulating neurofilament light is a biomarker that is responsive to enzyme replacement therapy (ERT) in CLN2 disease.
Methods:
Using an ultrasensitive immunoassay, we assessed plasma neurofilament light changes during disease progression in a canine model of CLN2 disease and in ERT clinical trial CLN2 disease patients.
Results:
In tripeptidyl peptidase 1 (TPP1)-null dogs (N = 11), but not in control dogs [N = 6 (TPP1+/- ) and N = 27 (WT)], neurofilament light levels increased more than tenfold above initial low baseline levels during disease progression. Before treatment in 21 human subjects with CLN2 disease (age range: 1.72-6.85 years), neurofilament light levels were 48-fold higher (P < 0.001) than in 7 pediatric controls (age range: 8-11 years). Pretreatment neurofilament light did not significantly correlate with disease severity or age. In CLN2 disease subjects receiving ERT, neurofilament light levels decreased by 50% each year over more than 3 years of treatment.
Interpretation:
Our data indicate that circulating neurofilament light is a treatment-responsive biomarker in CLN2 disease and could contribute to understanding of the pathophysiology of this devastating pediatric disorder.
Insights
Neurofilament light levels increase with Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) progression. Enzyme replacement therapy (ERT) significantly reduced these levels, indicating neurofilament light is a responsive biomarker for CLN2 disease.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a fatal, progressive neurodegenerative disorder in children caused by mutations in the TPP1 gene, leading to deficiencies in tripeptidyl peptidase 1.
- Identifying reliable biomarkers is crucial for monitoring CLN2 disease progression and evaluating the effectiveness of therapeutic interventions.
- Neurofilament light (NfL), a component of neurons, is elevated in the circulation during neuropathology in various adult neurological conditions.
Purpose of the Study:
- To investigate whether circulating neurofilament light (NfL) serves as a responsive biomarker for CLN2 disease.
- To assess the potential of NfL as a biomarker for tracking disease progression and response to enzyme replacement therapy (ERT) in CLN2 disease.
Main Methods:
- Plasma NfL levels were measured using an ultrasensitive immunoassay.
- Measurements were taken during disease progression in a canine model of CLN2 disease and in human patients undergoing ERT.
- Comparisons were made between CLN2 disease subjects, healthy controls, and TPP1-deficient canines.
Main Results:
- In TPP1-null dogs, NfL levels increased more than tenfold during disease progression.
- Human subjects with CLN2 disease exhibited NfL levels 48-fold higher than pediatric controls before treatment.
- During over three years of ERT, NfL levels in CLN2 disease patients decreased by approximately 50% annually.
Conclusions:
- Circulating neurofilament light (NfL) is a treatment-responsive biomarker in CLN2 disease.
- NfL levels can reflect disease progression and therapeutic response in CLN2 disease.
- This finding aids in understanding the pathophysiology of CLN2 disease and evaluating treatment efficacy.
