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

Abstract

Classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is caused by a deficiency of tripeptidyl-peptidase-1. In 2017, the first CLN2 enzyme replacement therapy (ERT) cerliponase alfa (Brineura) was approved by the FDA and EMA. The CLN2 disease clinical rating scale (CLN2 CRS) was developed to monitor loss of motor function, language and vision as well as frequency of generalised tonic clonic seizures. Using CLN2 CRS in an open label clinical trial it was shown that Brineura slowed down the progression of CLN2 symptoms. Neurofilament light chain (NfL) is a protein highly expressed in myelinated axons. An increase of cerebrospinal fluid (CSF) and blood NfL is found in a variety of neuroinflammatory, neurodegenerative, traumatic, and cerebrovascular diseases. We analysed CSF NfL in CLN2 patients treated with Brineura to establish whether it can be used as a possible biomarker of response to therapy. Newly diagnosed patients had CSF samples collected and analysed at first treatment dose and up to 12 weeks post-treatment to look at acute changes. Patients on a compassionate use programme who were already receiving ERT for approximately 1yr had CSF samples collected and NfL analysed over the following 1.3 years (2.3 years post-initiation of ERT) to look at long-term changes. All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels >2000 pg/ml at start of treatment. No significant change was observed in NfL up to 12 weeks post-treatment. After one year of ERT, two out of six patients still had high NfL levels, but all patients showed a continued decrease, and all had low NfL levels after two years on ERT. NfL levels appear to correspond and predict improved clinical status of patients on ERT and could be useful as a biomarker to monitor neurodegeneration and verify disease modification in CLN2 patients on ERT.

Biofluid‐based biomarkers for Alzheimer's disease–related pathologies: An update and synthesis of the literature

“…Antisense‐mediated silencing of huntingtin did not translate into any discernible clinical benefit and CSF NfL did not normalize (in fact, it increased in the high‐dose group, potentially pinpointing a side effect) 51 . It has become clear that NfL might be a very slow biomarker in some conditions; it took 2 to 3 years for CSF NfL concentration to decline in children with enzyme replacement therapy against neuronal ceroid lipofuscinosis 52 . In anti‐Aβ antibody trials, attenuated increases of CSF NfL have been reported, 53,54 which may indicate a positive effect on neurodegeneration by the treatment, although longer and larger studies are needed.…”

Preclinical studies in Krabbe disease: A model for the investigation of novel combination therapies for lysosomal storage diseases

“…However, a recent study developed guidelines that significantly reduced the risk of these adverse events. 137 , 148 Given these recent advances in ERT for CNS LSDs, ERT could be an important component of their treatment in the future.…”