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January 2023; 10 (1) Research ArticleOpen Access

Senescent-like Blood Lymphocytes and Disease Progression in Amyotrophic Lateral Sclerosis

Ozlem Yildiz, Johannes Schroth, Timothy Tree, Martin R. Turner, Pamela J. Shaw, Sian M. Henson, Andrea Malaspina
First published November 2, 2022, DOI: https://doi.org/10.1212/NXI.0000000000200042
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Article Information

vol. 10 no. 1 e200042
DOI: 
https://doi.org/10.1212/NXI.0000000000200042
PubMed: 
36323511
Published By: 
Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
Online ISSN: 
2332-7812
History: 
  • Received April 18, 2022
  • Accepted in final form August 22, 2022
  • First Published November 2, 2022.
Copyright & Usage: 
Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Author Disclosures

    1. Ozlem Yildiz, MD,
    2. Johannes Schroth,
    3. Timothy Tree, PhD,
    4. Martin R. Turner, PhD,
    5. Pamela J. Shaw, PhD,
    6. Sian M. Henson, PhD and
    7. Andrea Malaspina, PhD
  1. Ozlem Yildiz, MD,
    2. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. Received funding from the MND Association UK.

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  2. Johannes Schroth,
    3. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  3. Timothy Tree, PhD,
    4. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. (1) Diabetologia, Editorial Board, 2019-2022

    Patents:

    1. (1) patent (B75649EPD40021) pending on the use of low dose IL-2 for the treatment of ALS

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. (1) Galvani Biosciences (2) Vertex (3) Provention Bio (3) Imcyse

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. (1) Galvani Biosciences (2) GSK (3) Sanofi (3) Imcyse

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. (1) Diabetes UK (2) Juvenile Diabetes Research Foundation (3) The Leona M. and Harry B. Helmsley Charitable Trust

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  4. Martin R. Turner, PhD,
    5. Scientific Advisory Boards:

    1. (1) Commercial entity. Currently serving on independent trial 'Endpoint Adjudication Committee' for Biogen Pharmaceuticals ATLAS study.

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. (1) Journal of Neurology, Neurosurgery and Psychiatry. Commissioning and Associate Editor. 2016-2021.

    Patents:

    1. (1) A peptide sequence for the identification of TDP-43 proteinopathies.

    Publishing Royalties:

    1. (1) The Brain - A Beginner's Guide, Oneworld 2006 (2) Motor Neuron Disease - A Care Manual, Oxford University Press 2010 (3) Oxford Textbook of Neuromuscular Disorders, Oxford University Press 2014 (4) Landmark Papers in Neurology, Oxford University Press 2015 (5) Fast Facts: Diagnosing ALS, Karger Press 2019

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  5. Pamela J. Shaw, PhD,
    6. Scientific Advisory Boards:

    1. Served on Scientific Advisory Board for the following companies: 1. Aclipse Therapeutics 2. QurALIS 3. Biogen 4. Benevolent AI 5. Quell Therapeutics

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. Editorial Board Member of the journal Amyotrophic Lateral Sclerosis and the Frontotemporal Lobar Degenerations from 2007.

    Patents:

    1. 1. Therapeutics for neurological disorders. Inventors Shaw PJ, Mead R, Higginbottom A, Barber SC (2010). Publication number WO2010046710 (A1) describing NRF2 activating compounds for treatment of neurodegenerative diseases. 2. Orphan drug designation for S-apomorphine in the treatment of amyotrophic lateral sclerosis granted 2012 by the European Medicines regulatory agency. 3. GB2516725 – A neck orthosis. Inventors: CJ McDermott, PJ Shaw and others. This patent covers the design of a fabric snood base onto which modular support elements can be added offering personalized adaptable support to the head and neck. Approved in 2015. 4. PCT/US2019/056996 - Treatment of Neurodegenerative diseases. Inventors: Ning Shan, Richard Mead, Laura Ferraiuolo, Pamela J Shaw. This covers the mechanism of action of a drug identified at SITraN for the treatment of neurodegenerative diseases, including ALS. Submitted in 2019. 5. PCT/US2019/056998 - Treatment of Neurodegenerative diseases. Inventors: Laura Ferraiuolo, Ning Shan, Pamela J Shaw. This covers the specific properties of a neuroprotective compound identified at SITraN. Submitted in 2019. 6. 36008 SRSF1: 1) "Treatment for MND" application number EP17730896.2, filed 24-10-2018, priority date 01-06-2016, publication number EP3430143. "Gene Therapy" application number US16304487, filed 26-11- 2018, priority date 01-06-2016, publication number US2019/0194660. Inventors: G Hautbergue, M Azzouz, A Whitworth, PJ Shaw. 7. Patent number: 20305241.0 Low dose interleukin 2 for the treatment of amyotrophic lateral sclerosis. Date of filing 06/03/2020. Inventors: G Bensimon, PN Leigh, T Tree, C Garlanda, M Locati, J Kirby, PJ Shaw, A Malaspina.

    Publishing Royalties:

    1. Brain's Diseases of the Nervous System 12th Edition. Editor M. Donaghy. Oxford University Press. Since 2008.

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. Consultancies undertaken for the following commercial entities: 1. Biogen Idec 2. Sanofi-Aventis 3. Cytokinetics Inc 4. Ono Pharma 5. Vertex Pharmaceuticals 6. Aclipse Therapeutics 7. Benevolent AI 8. Quell Therapeutics 9. QurALiS

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. PFIZER 2017 – 2020 The involvement of C9ORF72 mutations in ALS and FTD. UNIVERSITY OF SHEFFIELD KNOWLEDGE EXCHANGE AND BIOGEN IDEC 2019- 2020 Increasing the Clinical Utility of Repeat Mutation Testing with Next Generation Long-read Sequencing. BENEVOLENT AI 2019 -2021 Use of Source Data (Clinical and Omic Data) to Stratify Patients with Amyotrophic Lateral Sclerosis PI. SWAN BIO 2020-2022 Exploring novel secreted neuroprotective candidates in amyotrophic lateral sclerosis (ALS) using FunSel technology. PI QUELL THERAPEUTICS 2020-2022 Development of Treg cell therapies for amyotrophic lateral sclerosis (ALS). PI

    Research Support, Government Entities:

    1. MEDICAL RESEARCH COUNCIL CoEN PATHFINDER III 2018-2021 Developing preclinical and clinical biomarkers of Nrf2 pathway activation for application in neurodegenerative diseases. NIHR 2018- 2022 HICALS- A programme to develop and evaluate a complex intervention to achieve a high calorie diet in ALS (HighCALS). NIHR 2018- 2020 COMMEND - A feasibility study and randomised controlled of acceptance and COMmitment therapy for people with Motor nEuroNe Disease (COMMEND). MEDICAL RESEARCH COUNCIL CONFIDENCE IN CONCEPT 2020-2021 Evaluate the gene therapy efficacy of SRSF1 depletion for the treatment of C9ORF72- linked amyotrophic lateral sclerosis and frontotemporal dementia. MEDICAL RESEARCH COUNCIL DPFS 2020-2023 (MICA-M102 a combined NRF2 and HSF1 activator for the treatment of motor neuron disease. MEDICAL RESEARCH COUNCIL-LIFE ARC 2021-2025 Gene Therapy Innovation and Manufacturing Centre (GTIMC). Co- applicant. NIHR EME 127921 2021- 2025. Evaluation of Triumeq as a treatment for amyotrophic lateral sclerosis: The Lighthouse 2 UK Study Call: 18/56 Neurodegenerative Disorders. Co-applicant.

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. EU HORIZON 2020 PHC 13 2014 -2021. MIROCALS (modifying immune response and outcomes in ALS). Efficacy and safety of low-dose IL-2 (Id-IL-2) as a Treg enhancer for anti-inflammatory therapy in newly diagnosed amyotrophic lateral sclerosis (ALS) patients. Multicentre study PJ Shaw Sheffield PI. (633413).MOTOR NEURONE DISEASE ASSOCIATION 2016-2022. A multicentre biomarker resource strategy in ALS: AMBRoSIA. with Martin Turner (Oxford) and Dr Andrea Malaspina (London).MOTOR NEURONE DISEASE ASSOCIATION 2016-2022 NECTAR. Co-PI.MOTOR NEURONE DISEASE ASSOCIATION 2017 – 2021. Renewal of Care and Research Centre for Motor Neuron Disorders. European Innovative Training Network: EURONeurotrophin 2018 – 2022. MOTOR NEURONE DISEASE ASSOCIATION 2017 – 2021 Utilizing the C9ORF72 zebrafish model of MND to identify and validate a novel disease modifying therapy. Co-applicant with Tennore Ramesh and Guillaume Hautbergue. WELLCOME TRUST 2018-2020. Characterising astrocyte metabolic defects in sporadic and familial Alzheimer’s disease to identify new therapeutic targets. LIFEARC PHILANTHROPIC FUND 2019 – 2022 £470,066 Gene replacement therpay for spastic paraplegia 47. WELLCOME TRUST 2020-2023. Identifying and verifying non-coding genetic causes of amyotrophic lateral sclerosis. Clinician Scientist award to Dr Johnathan Cooper-Knock. Sponsor. MY NAME'5 DODDIE FOUNDATION 2018-2021 Clinical trials infrastructure fund. EU Innovative Medicines Initiative (IMI) 2020-2025 (£ 22,227,210). Accelerating research and development for advanced therapies (ARDAT). Involves 23 academic and biotech European institutions and 11 major pharma companies. Co-applicant and Work Package 4 lead. FightMND 2020-2022 Australia Development of M102 for the treatment of MND. MOTOR NEURONE DISEASE ASSOCIATION 2020- 2023 Longitudinal Multi- omics of host-microbiome dynamics in amyotrophic lateral sclerosis. LIFE ARC 2021-2024 SRSF1-targeted gene therapy for C9ORF72-linked Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. MOTOR NEURONE DISEASE ASSOCIATION 2021- 2025 enewal of Sheffield Care and Research Centre for motor neuron disorders. DARBY RIMMER MND FOUNDATION 2021-2023. Development, validation and application of a novel multiplexed cell-based drug screening assay to discover novel drug candidates focused on restoring protein homeostasis in C9ALS/FTD. MOTOR NEURONE DISEASE ASSOCIATION 2021- 2022. Gene Expression Profiling to Establish the Longitudinal and Participant Specific Effects of Low- Dose Interleukin-2 in the Blood throughout the MIROCALS Clinical Trial.

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  6. Sian M. Henson, PhD and
    7. Scientific Advisory Boards:

    1. None

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. None

    Editorial Boards:

    1. NONE

    Patents:

    1. NONE

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. NONE

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. NONE

    Research Support, Government Entities:

    1. NONE

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. None

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  7. Andrea Malaspina, PhD
    8. Scientific Advisory Boards:

    1. Travel grant of £ 2500 from the Australian Neuroscience Society to cover the expenses for attendance to the ANS 2019 and MND Association Symposium in Australia, 01-07 December 2019

    Gifts:

    1. NONE

    Funding for Travel or Speaker Honoraria:

    1. “Monitoring Neuroplasticity: biomarkers of neurodegeneration”. Neuroplasticity: nerve cells do regenerate. Riga, Latvia, Society of Neuroscience, 13-15 April, 2018. Speaker JSC Olainfarm £ 2000 plus travel and Hotel expenses

    Editorial Boards:

    1. NONE

    Patents:

    1. U.S. Provisional Patent Application No. 62/511,595, Inventors: Benatar, Malaspina; Title: Determining Onset of Amyotrophic Lateral Sclerosis. Univ. Miami Reference: UMIP-142. MG Reference: 32286/51952/US MIROCALS patent co-ownership, application 06/03/2020 - international publication date 10.09.2021 - WO2021/176044A1

    Publishing Royalties:

    1. NONE

    Employment, Commercial Entity:

    1. NONE

    Consultancies:

    1. NONE

    Speakers' Bureaus:

    1. NONE

    Other Activities:

    1. Seminar given to " ES&I Weekly Seminar", Pfizer, 22.07.2020.

    Clinical Procedures or Imaging Studies:

    1. NONE

    Research Support, Commercial Entities:

    1. “Immunoreactivity to neurofilaments: therapeutics and biomarkers for ALS” Barts and the London Charity, UCB Pharma SPRL £ 133,769

    Research Support, Government Entities:

    1. “Pre-Symptomatic ALS – Prelude to a Disease Prevention Trial NIH- 95258”; £152,560 Clinical trial readiness in ALS National Institutes of Health - USA NIH-U01 Multi-PI grant award $ 367,372

    Research Support, Academic Entities:

    1. NONE

    Research Support, Foundations and Societies:

    1. ALSA / CReATe 17-CReA-382, Strategic Initiative Malaspina (PI) 10/31/2016-30/09/2017 “Going Dry – Empowering neurofilament-based biomarker studies for disease monitoring in ALS”. “Triumeq“. MND Association Gold / Jul 17/912 -793 PI. Biomarkers analysis 01.10.2017 to 31.11.2017

    Stock/Stock Options/Board of Directors Compensation:

    1. NONE

    License Fee Payments, Technology or Inventions:

    1. NONE

    Royalty Payments, Technology or Inventions:

    1. NONE

    Stock/Stock Options, Research Sponsor:

    1. NONE

    Stock/Stock Options, Medical Equipment & Materials:

    1. NONE

    Legal Proceedings:

    1. NONE

  1. From the Neuroscience and Trauma Centre (O.Y., A.M.), Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London; Queen Square Motor Neuron Disease Centre (A.M.), Neuromuscular Department, Institute of Neurology, University College London; Translational Medicine and Therapeutics (J.S., S.M.H.), William Harvey Research Institute, Barts and the London, Queen Mary University of London; Department of Immunobiology (T.T.), School of Immunology & Microbial Sciences, King's College London; Nuffield Department of Clinical Neurosciences (M.R.T.), University of Oxford; and Sheffield Institute for Translational Neuroscience (P.J.S.), University of Sheffield, UK.
  1. Correspondence
    Dr. Malaspina a.malaspina{at}ucl.ac.uk
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