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

November 25, 2025 updated by: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
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.

Study Overview

Status

Recruiting

Conditions

Detailed Description

The absence of specific biomarkers poses a significant impediment to the advancement of new treatments for amyotrophic lateral sclerosis (ALS), a severe and rapidly fatal neurodegenerative disease with no cure to date, defined by degeneration of motor neurons. Early pathological events, such as the selective damage of motor axons and the loss of neuromuscular connections, precede complete neurodegeneration and the manifestation of clinical symptoms. Therefore, we argue that understanding disease-related changes occurring in peripheral nerves is crucial for defining the underlying pathogenetic mechanisms. Preliminary data from our research team suggest that phosphorylated TDP-43, the pathological hallmark of ALS, forms aggregates in motor axons and Schwann cells of living ALS patients before the onset of axonal degeneration. However, peripheral nerves constitute complex multicellular tissues, and the specific contributions of individual cellular components to ALS pathology remain poorly understood. The overarching concept of this proposal is that distinct cell types within the nerve tissue (e.g., Schwann cells, endothelial cells, fibroblasts, macrophages) function as exquisite early detectors of motor neuron damage and initiate secondary responses that amplify neuropathology. These studies will steer the analysis of minimally invasive skin biopsies to uncover deregulated PNS signatures in ALS patients. Finally, candidate molecular targets reflecting cell-type-specific deregulation in the diseased nerve microenvironment will be screened in the biofluids of ALS patients and at-risk individuals from genetic ALS families, enabling the discovery of novel diagnostic and prognostic biomarkers. The integrative approach proposed in this study will elucidate the pathogenic mechanisms of ALS and establish a roadmap towards identifying potential therapeutic targets.

Study Type

Observational

Enrollment (Estimated)

400

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Milan, Italy
        • Recruiting
        • Fondazione IRCCS Istituto Neurologico Carlo Besta
        • Contact:
      • Milan, Italy
      • Napoli, Italy, 80131
        • Recruiting
        • Azienda Ospedaliera Universitaria Federico II
        • Contact:
    • California
      • Monserrato, California, Italy, 09042
        • Recruiting
        • Azienda Ospedaliero Universitaria di Cagliari
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

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.

Description

Inclusion Criteria for als patients:

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

Exclusion Criteria for als patients:

  • FVC <60%;
  • nutritional or respiratory failure;
  • significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.

Inclusion criteria for ALS pre-symptomatic patients

  • Age equal or over 18 years old
  • Patients with genetic defined susceptibility to ALS and one or more strict relative affected from ALS Exclusion criteria for ALS pre-symptomatic patients
  • significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.

Inclusion criteria for controls

  • Age equal or over 18 years old
  • Subjects without a diagnosis of neurodegenerative disease or neuromuscular disorder.

Exclusion criteria for controls

• significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.

Inclusion criteria for non ALS neurodegenerative patients

  • 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
  • For DLB: Diagnosis according to 2017 Fourth Consensus Report of the DLB Consortium Exclusion criteria for non ALS neurodegenerative patients
  • significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.

Inclusion criteria for neuromuscular disease patients

  • Age equal or over 18 years old
  • Presence of axonal or demyelinating neuropathy Exclusion criteria for neuromuscular patients
  • significant hepatic or chronic renal failure or any interveninginfective or metabolic conditions potentially influencing CBs levels.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
1
ALS patients
2
Neuropathy patients
3
presymptomatic patients
4
healthy controls
5
Other neurodegenerative diseases

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Diagnostic ALS biomarkers
Time Frame: 20 months
Throughout the study, we will validate, starting from transcriptomics data, novel diagnostic biomarker for an early diagnosis of ALS
20 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prognostic biomarkers
Time Frame: 24 months
explore novel prognostic biomarkers, able to reliably predict the time-course of ALS
24 months
Therapeutic targets
Time Frame: 24 months
identify molecular targets related to axonal degeneration for potential therapeutic intervention
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Collaborators

IRCCS San Raffaele
Azienda Ospedaliero Universitaria di Cagliari
Università di Napoli Federico II

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 24, 2024

Primary Completion (Estimated)

April 1, 2027

Study Completion (Estimated)

April 1, 2027

Study Registration Dates

First Submitted

November 25, 2025

First Submitted That Met QC Criteria

November 25, 2025

First Posted (Actual)

December 8, 2025

Study Record Updates

Last Update Posted (Actual)

December 8, 2025

Last Update Submitted That Met QC Criteria

November 25, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PNRR-MCNT2-2023-12377651

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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