{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:10:36Z","timestamp":1772169036775,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/f1000research.54556.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T00:00:00Z","timestamp":1641340800000}}],"reference-count":14,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T00:00:00Z","timestamp":1641340800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019256","name":"NIHR Great Ormond Street Hospital Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019256","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Battens Disease Research and Support Association"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>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.<\/ns3:p>\n                  <ns3:p>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.<\/ns3:p>\n                  <ns3:p>All newly diagnosed patients we investigated with classical late infantile phenotype had high NfL levels &gt;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.<\/ns3:p>","DOI":"10.12688\/f1000research.54556.2","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T08:55:07Z","timestamp":1641372907000},"page":"614","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Cerebrospinal fluid neurofilament light chain levels in CLN2 disease patients treated with enzyme replacement therapy normalise after two years on treatment"],"prefix":"10.12688","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5223-0620","authenticated-orcid":false,"given":"Katharina","family":"Iwan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7290-6405","authenticated-orcid":false,"given":"Amanda","family":"Heslegrave","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mina","family":"Borisova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Bower","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4385-4957","authenticated-orcid":false,"given":"Sara E.","family":"Mole","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippa B.","family":"Mills","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0763-8288","authenticated-orcid":false,"given":"Kevin","family":"Mills","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Gissen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-8760","authenticated-orcid":false,"given":"Wendy E.","family":"Heywood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2022,1,5]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"315-325","DOI":"10.1007\/s40263-019-00620-8","article-title":"Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses.","volume":"33","author":"A Kohlsch\u00fctter","year":"2019","journal-title":"CNS Drugs"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"9592-9604","DOI":"10.1074\/jbc.RA119.008852","article-title":"Lysosomal proteome analysis reveals that CLN3-defective cells have multiple enzyme deficiencies associated with changes in intracellular trafficking.","volume":"294","author":"C Schmidtke","year":"2019","journal-title":"J Biol Chem"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"213-222","DOI":"10.2147\/TCRM.S241048","article-title":"Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy.","volume":"16","author":"N Specchio","year":"2020","journal-title":"Ther Clin Risk Manag"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1898-1907","DOI":"10.1056\/NEJMoa1712649","article-title":"Study of Intraventricular Cerliponase Alfa for CLN2 Disease.","volume":"378","author":"A Schulz","year":"2018","journal-title":"N Engl J Med"},{"key":"ref6","first-page":"1-7","article-title":"Jacoby and Alfried Kohlsch\u00fctter. An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease.","volume":"6","author":"W Kathleen","year":"2018","journal-title":"J Inborn Errors Metabolism Screening."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"577-589","DOI":"10.1038\/s41582-018-0058-z","article-title":"Neurofilaments as biomarkers in neurological disorders.","volume":"14","author":"M Khalil","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1247-1249","DOI":"10.1007\/s40265-017-0771-8","article-title":"Cerliponase Alfa: First Global Approval.","volume":"77","author":"A Markham","year":"2017","journal-title":"Drugs"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"751-757","DOI":"10.1038\/s41436-020-01035-3","article-title":"Neurofilament light chain levels correlate with clinical measures in CLN3 disease.","volume":"23","author":"A Dang Do","year":"2021","journal-title":"Genet Med: official journal of the American College of Medical Genetics"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"2437-2447","DOI":"10.1002\/acn3.50942","article-title":"Neurofilament light is a treatment-responsive biomarker in CLN2 disease.","volume":"6","author":"Y Ru","year":"2019","journal-title":"Ann Clin Transl Neurol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"e0135886","DOI":"10.1371\/journal.pone.0135886","article-title":"Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction.","volume":"10","author":"M Vagberg","year":"2015","journal-title":"PloS One"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"579958","DOI":"10.3389\/fnins.2020.579958","article-title":"Serum Neurofilament Levels in Children With Febrile Seizures and in Controls.","volume":"14","author":"K Evers","year":"2020","journal-title":"Front Neurosci"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12366","article-title":"Seizure phenotype in CLN3 disease and its relation to other neurologic outcome measures.","author":"M Abdennadher","year":"2021","journal-title":"J Inherit Metab Dis."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e12099","DOI":"10.1002\/dad2.12099","article-title":"Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer's disease.","volume":"12","author":"L Raket","year":"2020","journal-title":"Alzheimers Dement (Amst)"},{"key":"ref15","article-title":"CSF Nfl results CLN2 disease Iwan etal.","author":"K Iwan","year":"2021","journal-title":"UCL data repository."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/10-614\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-614\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/10-614\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T04:00:22Z","timestamp":1642651222000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/10-614\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,5]]},"references-count":14,"URL":"https:\/\/doi.org\/10.12688\/f1000research.54556.2","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.80101.r118695","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.80101.r118695","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,5]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/10-614\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.80101.r118695, Michel Boutin, Division of Medical Genetics, Department of Pediatrics, Centre de Recherche-CHUS, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC, Canada, 20 Jan 2022, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/10-614\/v2#referee-response-118695","order":0,"name":"referee-response-118695","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.58055.r96195, Daniel Erskine, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK, 09 Nov 2021, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/10-614\/v1#referee-response-96195","order":1,"name":"referee-response-96195","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Wendy Heywood<\/b>; \n<i>Posted: 03 Dec 2021<\/i>; \n<i>Many thanks for reviewing the report. We tried to analyse whether the speed of loss of points on CLN2 clinical score is correlated with the slope of NFL normalisation, i.e. whether NFL levels can act as a biomarker of response to enzyme replacement therapy (ERT). We did indeed look at this and did not find a statistically significant correlation. This could be due to a few factors such as the small number of patients in the study, the fact that CLN2 score is not sufficiently sensitive to detect small changes in response or there is no real correlation between the NFL levels and the patients response to ERT. <\/i>  \n<i>In response ot your other question the MRI scans are performed yearly in the patients which is similar to the clinical trial previously reported by Schulz et al. NEJM 2018, where MRI grey matter volume changes was one of the outcome measures. The results in our patients were in line with the clinical trial report where patients lost approximately 10.5% of total grey matter volume in the first year of treatment and 3.3%in the second year which indeed indicates neurodegenerative processes. <\/i>","URL":"https:\/\/f1000research.com\/articles\/10-614\/v2#referee-comment-7539","order":2,"name":"referee-comment-7539","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This study has been funded by the Batten Disease Support and Research Association (BDSRA) and Great Ormond Street Biomedical Research centre.   Medical Research Council (Grant No MR\/R025134\/1) supported research (S.E.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}