A Patient-tailored Genetic/Biomarker/iPSC Combined Approach in ALS - PERMEALS

NCT06917924 | Recruiting

• 1 other identifier: PNRR-MAD-2022-12375731
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 4

Brief Summary

Amyotrophic Lateral Sclerosis (ALS) is a severe and incurable neurodegenerative disease of motor neurons with a dramatic socio-economic impact on the national health system. ALS is a complex disorder with the majority of cases being sporadic and about 15% of cases showing familial history. It is characterized by high genetic heterogeneity, with more than 30 causative genes accounting for 60% of familial and 10% of sporadic cases. The clinical manifestations of ALS are variable with respect to age and site of onset, disease progression, relative upper versus lower motor neuron involvement, genetic background, and the occurrence of cognitive and behavioral change. This remains the case in those families with known disease-causing variants, suggesting that additional disease-modifying factors exist. A variety of wet biomarkers, including neurofilaments and extracellular vesicles, hold great promise in predicting the development of the disease and the variability in its progression. Neuroimaging techniques have been demonstrated to be able to detect abnormalities in motor and non-motor areas with a variety of patterns that reflect disease severity, progression, and duration. Disease heterogeneity is likely underpinned by the presence of different pathogenic mechanisms that can be studied at a molecular level in preclinical models. Human-induced pluripotent stem cells (iPSC) and derived motor neurons have shown functional disease-relevant phenotypes and seem to be particularly useful in modeling the heterogeneity of human ALS. All these pieces of information scattered in different studies have not been combined to drive research toward personalized medicine. In this project, the investigators gathered a team of exceptional and specific expertise in all these aspects of ALS research. The research group will perform an in-depth characterization of the clinical, neuroradiological, genetic, and biochemical levels of a cohort of ALS patients. In particular, researchers will measure selected established biomarkers mirroring fundamental pathophysiological processes in ALS such as neuroaxonal degeneration, alterations in protein homeostasis, TDP-43 pathology, neuroinflammation, and cell-cell communication. The investigators will also use neuroimaging techniques to highlight the structural and functional correlates of neurodegeneration in ALS. Next, researchers will integrate all these data by using artificial intelligence approaches with the aim of identifying different signatures that can be modeled in vitro in patient-derived iPSC. The investigators are confident that the PERMEALS project, by using a combined multi-angled approach, will represent the first step toward a personalized medicine to cure ALS.

Conditions

Amyotrophic Lateral Sclerosis (ALS)

Outcome Measures

Primary Outcomes (5)

• Clinical classification of the patients using international ALS phenotype criteria

  No. of patients with classic, predominant upper, predominant lower, bulbar, flail arm, flail leg, cachectic, PLS, PMA phenotypes

  At baseline and after 12 months

• Perform a cognitive classification of the patient

  Verify the presence of cognitive impairment/ language or executive dysfunction in ALS patients using the neuropsychological assessment battery in particular ECAS score

  At baseline, after 6 months, and after 12 months

• Perform genetic characterization of the patients

  Perform NGS analysis on recruited patients to identify genetic variants associated with ALS susceptibility

  At baseline

• Evaluation of potential biomarkers in biofluids obtained from patients

  No. of patients with abnormal NFL, tau, UCHL1, PPIA, TDP-43, MCP-1, GFAP, MMP-9, PPIA levels in plasma and cerebrospinal fluid from patients.

  At baseline, after 6 months, and after 12 months

• Evaluation MRI features

  These models, including the GuanRank model and a Random forest analysis, will be used to identify brain MRI and molecular variables that best predict the cognitive and behavioral scores and physical disability (i.e. phenotypic heterogeneity) and disease prognosis.

  At baseline, after 6 months, and after 12 months for MRI

Secondary Outcomes (2)

• Generation of patient-derived iPSCs from peripheral blood mononuclears cells (PBMC) or primary fibroblasts.

  At baseline

• Evaluation of FDG-PET features

  At baseline

Interventions

lumbar puncture DIAGNOSTIC_TEST

Standard of care of LP

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

ALS patients enrolled in CRESLA of Torino, ALS center of Istituto Auxiologico of Milano, and ALS center ov University of Napoli Vanvitelli

You may qualify if:

• Diagnosis of ALS

You may not qualify if:

• ALS patients under 18 years old

Sponsors & Collaborators

• A.O.U. Città della Salute e della Scienza: lead

Study Sites (4)

IRCCS Istituto Auxologico Italiano

Milan, 20149, Italy

RECRUITING

Istituto di Ricerche Farmacologiche Mario Negri IRCCS

Milan, 20156, Italy

RECRUITING

Università degli Studi della Campania "Luigi Vanvitelli"

Napoli, 80138, Italy

RECRUITING

AOU Citta della Salute e della Scienza di Torino

Torino, 10126, Italy

RECRUITING

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

Spinal Puncture

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Biopsy; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Neurological; Punctures; Therapeutics; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Associate Professor

Study Record Dates

• First Submitted: March 12, 2025
• First Posted: April 9, 2025
• Study Start: May 20, 2023
• Primary Completion: May 20, 2025
• Study Completion: November 20, 2025
• Last Updated: April 9, 2025

Record last verified: 2025-03

Locations

IT (4)