Translating Single-cell Vulnerability Into Novel ALS Biomarkers and Therapeutic Targets: Towards a Liquid Nerve Biopsy

NCT07268833 | Recruiting

• 1 other identifier: PNRR-MCNT2-2023-12377651
• Study Type: observational
• Target: 400
• Locations: 1 country
• Sites: 4

Brief Summary

The progress of ALS research and clinical practice is hampered by lack of effective biomarkers to monitor disease onset and progression. In response to this urgent need, we will integrate single-cell system biology approaches, histopathological and clinical data from precious human nerve biopsies collected from living ALS patients during the diagnostic workup and findings from innovative preclinical mouse models to unmask cell-specific molecular alterations that arise in the PNS tissue during the course of ALS pathology. This information will be used to select protein biomarkers of dysfunctional states associated with pre-manifest or early symptomatic stages of the disease, which will be further screened and validated in patient biofluids. Altogether, this project will lead to the discovery of novel, reliable and specific ALS biomarkers while providing insights into ALS mechanisms by leveraging an original "PNS perspective" on disease pathogenesis.

Conditions

Peripheral Neuropathies; Amyotrophic Lateral Sclerosis (ALS)

Keywords

ALS; Peripheral Neuropathies; Motor Neuron Disease; Biomarkers; Neurodegeneration; Nerve Biopsy; skin biopsy; Spatial Transcriptomics

Outcome Measures

Primary Outcomes (1)

• Diagnostic ALS biomarkers

  Throughout the study, we will validate, starting from transcriptomics data, novel diagnostic biomarker for an early diagnosis of ALS

  20 months

Secondary Outcomes (2)

• Prognostic biomarkers

  24 months

• Therapeutic targets

  24 months

Study Arms (5)

1

ALS patients

2

Neuropathy patients

3

presymptomatic patients

4

healthy controls

5

Other neurodegenerative diseases

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Number of patients projected for: * the entire study: 400 patients * each treatment group: ALS 150, HC 40, non-ALS neurodegenerative 60, non-ALS neuromuscular diseases 50, Indipendent cohort of ALS Sardinian patients 100.

You may qualify if:

• Age equal or over 18 years old
• ALS patients, diagnosed accordingly to the revised El Escorial Criteria
• Disease duration \<24 months from symptom onset.

You may not qualify if:

• FVC \<60%;
• nutritional or respiratory failure;
• significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.
• Age equal or over 18 years old
• significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.
• Age equal or over 18 years old
• Subjects without a diagnosis of neurodegenerative disease or neuromuscular disorder.
• significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.
• Age equal or over 18 years old
• For AD: Diagnosis according to 2018 NIA-AA Framework for Alzheimer's Disease
• For FTD: Diagnosis according to 2011 International Behavioural Variant FTD Criteria Consortium
• For PD: Diagnosis according to 2015 Movement Disorder Society criteria
• significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.
• Age equal or over 18 years old
• significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.

Sponsors & Collaborators

• Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta: lead
• Azienda Ospedaliero Universitaria di Cagliari: collaborator
• IRCCS San Raffaele: collaborator
• Università di Napoli Federico II: collaborator

Study Sites (4)

Azienda Ospedaliero Universitaria di Cagliari

Monserrato, California, 09042, Italy

RECRUITING

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, Italy

RECRUITING

IRCCS Ospedale San Raffaele SRL

Milan, Italy

RECRUITING

Azienda Ospedaliera Universitaria Federico II

Naples, 80131, Italy

RECRUITING

Related Publications (11)

• Rocha MC, Pousinha PA, Correia AM, Sebastiao AM, Ribeiro JA. Early changes of neuromuscular transmission in the SOD1(G93A) mice model of ALS start long before motor symptoms onset. PLoS One. 2013 Sep 5;8(9):e73846. doi: 10.1371/journal.pone.0073846. eCollection 2013.

  PMID: 24040091 BACKGROUND

• Riva N, Iannaccone S, Corbo M, Casellato C, Sferrazza B, Lazzerini A, Scarlato M, Cerri F, Previtali SC, Nobile-Orazio E, Comi G, Quattrini A. Motor nerve biopsy: clinical usefulness and histopathological criteria. Ann Neurol. 2011 Jan;69(1):197-201. doi: 10.1002/ana.22110. Epub 2010 Nov 12.

  PMID: 21280090 BACKGROUND

• Riva N, Gentile F, Cerri F, Gallia F, Podini P, Dina G, Falzone YM, Fazio R, Lunetta C, Calvo A, Logroscino G, Lauria G, Corbo M, Iannaccone S, Chio A, Lazzerini A, Nobile-Orazio E, Filippi M, Quattrini A. Phosphorylated TDP-43 aggregates in peripheral motor nerves of patients with amyotrophic lateral sclerosis. Brain. 2022 Mar 29;145(1):276-284. doi: 10.1093/brain/awab285.

  PMID: 35076694 BACKGROUND

• Riva N, Clarelli F, Domi T, Cerri F, Gallia F, Trimarco A, Brambilla P, Lunetta C, Lazzerini A, Lauria G, Taveggia C, Iannaccone S, Nobile-Orazio E, Comi G, D'Antonio M, Martinelli-Boneschi F, Quattrini A. Unraveling gene expression profiles in peripheral motor nerve from amyotrophic lateral sclerosis patients: insights into pathogenesis. Sci Rep. 2016 Dec 16;6:39297. doi: 10.1038/srep39297.

  PMID: 27982123 BACKGROUND

• Nolano M, Provitera V, Manganelli F, Iodice R, Caporaso G, Stancanelli A, Marinou K, Lanzillo B, Santoro L, Mora G. Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy. Neuropathol Appl Neurobiol. 2017 Feb;43(2):119-132. doi: 10.1111/nan.12332. Epub 2016 Jul 7.

  PMID: 27288647 BACKGROUND

• Gentile F, Scarlino S, Falzone YM, Lunetta C, Tremolizzo L, Quattrini A, Riva N. The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research. Front Neurosci. 2019 Jun 25;13:601. doi: 10.3389/fnins.2019.00601. eCollection 2019.

  PMID: 31293369 BACKGROUND

• Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004 Feb;185(2):232-40. doi: 10.1016/j.expneurol.2003.10.004.

  PMID: 14736504 BACKGROUND

• Casiraghi V, Milone I, Brusati A, Peverelli S, Doretti A, Poletti B, Maderna L, Morelli C, Ticozzi N, Silani V, Verde F, Ratti A. Quantification of serum TDP-43 and neurofilament light chain in patients with amyotrophic lateral sclerosis stratified by UNC13A genotype. J Neurol Sci. 2024 Nov 15;466:123210. doi: 10.1016/j.jns.2024.123210. Epub 2024 Sep 2.

  PMID: 39241471 BACKGROUND

• Brodovitch A, Boucraut J, Delmont E, Parlanti A, Grapperon AM, Attarian S, Verschueren A. Combination of serum and CSF neurofilament-light and neuroinflammatory biomarkers to evaluate ALS. Sci Rep. 2021 Jan 12;11(1):703. doi: 10.1038/s41598-020-80370-6.

  PMID: 33436881 BACKGROUND

• Bhat GP, Maurizio A, Motta A, Podini P, Diprima S, Malpighi C, Brambilla I, Martins L, Badaloni A, Boselli D, Bianchi F, Pellegatta M, Genua M, Ostuni R, Del Carro U, Taveggia C, de Pretis S, Quattrini A, Bonanomi D. Structured wound angiogenesis instructs mesenchymal barrier compartments in the regenerating nerve. Neuron. 2024 Jan 17;112(2):209-229.e11. doi: 10.1016/j.neuron.2023.10.025. Epub 2023 Nov 15.

  PMID: 37972594 BACKGROUND

• Barrientos SA, Martinez NW, Yoo S, Jara JS, Zamorano S, Hetz C, Twiss JL, Alvarez J, Court FA. Axonal degeneration is mediated by the mitochondrial permeability transition pore. J Neurosci. 2011 Jan 19;31(3):966-78. doi: 10.1523/JNEUROSCI.4065-10.2011.

  PMID: 21248121 BACKGROUND

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis; Peripheral Nervous System Diseases; Motor Neuron Disease; Nerve Degeneration

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2025
• First Posted: December 8, 2025
• Study Start: October 24, 2024
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027
• Last Updated: December 8, 2025

Record last verified: 2025-11

Locations

IT (4)