Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment

F1000Res. 2021 Jul 20;10:614. doi: 10.12688/f1000research.54556.2.

PMID: 35106137

Katharina Iwan, Nina Patel, Amanda Heslegrave

Highlights: In this study, it is aimed to analyze CSF NfL in CLN2 patients treated with Cerliponase alfa (Brineura) to establish whether it can be used as a possible biomarker of response to therapy.

Abstract

Background: Tripeptidyl-peptidase-1 deficiency results in classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease). Cerliponase alfa (Brineura), the first CLN2 enzyme replacement therapy (ERT), received FDA and EMA approval in 2017. The CLN2 disease clinical rating scale (CLN2 CRS) was created to track generalized tonic-clonic seizures frequency as well as loss of motor function, language, and vision. Brineura was demonstrated to reduce the progression of CLN2 symptoms in an open label clinical trial using CLN2 CRS. In myelinated axons, the protein known as neurofilament light chain (NfL) is extensively expressed. Numerous neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular disorders are characterized by a rise in cerebrospinal fluid (CSF) and blood NfL.

Objective: In order to determine whether CSF NfL may be used as a potential biomarker of therapeutic response in CLN2 patients treated with Brineura, CSF NfL is analyzed in these patients.

Methods and results: CSF samples from newly diagnosed patients were taken and examined to check for acute alterations at the time of the first treatment dose and up to 12 weeks post treatment. CSF samples were taken from patients on a compassionate use program who had already been receiving ERT for about a year, and NfL was analyzed during the following 1.3 years (2.3 years post-initiation of ERT) to test for long-term alterations. At the beginning of treatment, all newly diagnosed patients with the classic late infantile phenotype that were checked at had high NfL levels >2000 pg/ml. NfL showed no apparent change up to 12 weeks after therapy. Two out of six patients still had high NfL levels after one year of ERT, while all other patients continued to exhibit a decline and all had low NfL levels after two years on ERT.

Conclusion: NfL levels could be used as a biomarker to monitor neurodegeneration and confirm disease modification in CLN2 patients on ERT. They also appear to correlate and predict improved clinical status of patients on ERT.

Keywords: Enzyme replacement therapy, Neurofilament light, Neuronal Ceroid lipofuscinosis