Role of Extracellular Vesicles as Biomarkers of Pulmonary Involvement in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex

December 12, 2025 updated by: Michele Mondoni, University of Milan

Prospective Observational Study of the Role of Extracellular Vesicles (EVs) as Biomarkers of Pulmonary Involvement in Patients With Sporadic Lymphangioleiomyomatosis (S-LAM) and Tuberous Sclerosis Complex-Associated LAM (TSC-LAM)

Lymphangioleiomyomatosis (LAM) is a rare lung disease, linked to Tuberous Sclerosis Complex (TSC) or occurring sporadically, and involves abnormal mTORC1 activation. LAM cells are neoplastic, and recent focus has turned to extracellular vesicles (EVs), which mediate tumor progression and may serve as biomarkers. This study, conducted at the Pulmonology Unit of ASST Santi Paolo e Carlo and the Pharmacology Laboratory of the University of Milan, will analyze the characteristics of serum EVs in patients with LAM and TSC. During scheduled outpatient visits, clinical and functional data and blood samples will be collected. Plasma will be separated, and EVs will be isolated via centrifugation. EVs will be analyzed for size, concentration, and molecular content (proteins, lipids, nucleic acids). The results obtained will be collected and correlated with the clinical and functional data.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Estimated)

80

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
    • Milano
      • Milan, Milano, Italy, 20142

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

Non-Probability Sample

Study Population

Female participants aged ≥18 years with a confirmed diagnosis of tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (LAM), followed at the Pulmonology Unit of ASST Santi Paolo e Carlo, Milan, and able to provide written informed consent.

Description

Inclusion Criteria:

Female participants aged ≥18 years Confirmed diagnosis of tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (definite diagnosis of TSC-LAM or S-LAM) Follow-up at the Pulmonology Unit of ASST Santi Paolo e Carlo, Milan Ability to provide written informed consent

Exclusion Criteria:

Diagnosis of "probable" or "possible" LAM Refusal to provide written informed consent

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
Intervention / Treatment
Control
Healthy subjects
Diagnostic test: Pulmonary Function Test
Spirometry, Plethysmography, Diffusing capacity of the lungs for carbon monoxide (DLCO), and Six-minute walk test (6MWT).
Diagnostic test: Analysis of Extracellular Vesicles
From the venous blood sample, plasma will be separated, and extracellular vesicles (EVs) will be isolated through serial centrifugation steps. The EVs will be analyzed to assess their concentration (particles/mL) and size (nanometers, nm). Additionally, omics analyses will be performed to study the molecular content of the EVs, including nucleic acids, proteins, and lipids.
S-LAM
Patients with sporadic LAM
Diagnostic test: Pulmonary Function Test
Spirometry, Plethysmography, Diffusing capacity of the lungs for carbon monoxide (DLCO), and Six-minute walk test (6MWT).
Diagnostic test: Analysis of Extracellular Vesicles
From the venous blood sample, plasma will be separated, and extracellular vesicles (EVs) will be isolated through serial centrifugation steps. The EVs will be analyzed to assess their concentration (particles/mL) and size (nanometers, nm). Additionally, omics analyses will be performed to study the molecular content of the EVs, including nucleic acids, proteins, and lipids.
TSC-LAM
Patients with TSC-associated LAM
Diagnostic test: Pulmonary Function Test
Spirometry, Plethysmography, Diffusing capacity of the lungs for carbon monoxide (DLCO), and Six-minute walk test (6MWT).
Diagnostic test: Analysis of Extracellular Vesicles
From the venous blood sample, plasma will be separated, and extracellular vesicles (EVs) will be isolated through serial centrifugation steps. The EVs will be analyzed to assess their concentration (particles/mL) and size (nanometers, nm). Additionally, omics analyses will be performed to study the molecular content of the EVs, including nucleic acids, proteins, and lipids.
TSC
Patients with TSC and no pulmonary involvement
Diagnostic test: Pulmonary Function Test
Spirometry, Plethysmography, Diffusing capacity of the lungs for carbon monoxide (DLCO), and Six-minute walk test (6MWT).
Diagnostic test: Analysis of Extracellular Vesicles
From the venous blood sample, plasma will be separated, and extracellular vesicles (EVs) will be isolated through serial centrifugation steps. The EVs will be analyzed to assess their concentration (particles/mL) and size (nanometers, nm). Additionally, omics analyses will be performed to study the molecular content of the EVs, including nucleic acids, proteins, and lipids.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To compare the number and morphological characteristics of Extracellular Vesicles (EVs) in women with S-LAM, TSC-LAM, TSC without pulmonary involvement, and healthy controls
Time Frame: One year
The concentration (particles/mL) and the size (nm) of EVs isolated from the plasma of 3 groups of patients (sporadic LAM, LAM associated to TSC, TSC without pulmonary involvement) and of 1 healthy control group will be assessed through Nanoparticle Tracking Analysis.
One year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To evaluate the content of EVs (miRNA, lipids, proteins, metabolites) through omics analyses in women with S-LAM, TSC-LAM, TSC without pulmonary involvement, and healthy controls
Time Frame: One year

The content of EVs isolated from the plasma of 3 groups of patients (plasma of 3 groups of patients (sporadic LAM, LAM associated to TSC, TSC without pulmonary involvement) and of 1 healthy control group will be assessed through

-omics analyses.
One year
Effect of mTOR-inhibitor therapy on EVs count
Time Frame: One year
The concentration (particles/mL) of extracellular vesicles (EVs) in patients with LAM treated with mTOR inhibitor therapy (sirolimus or everolimus) compared with patients not receiving mTOR inhibitor therapy will be assessed using Nanoparticle Tracking Analysis (NTA).
One year
Effect of mTOR-inhibitor therapy on EVs morphology
Time Frame: One Year
The size (nanometers, nm) of extracellular vesicles (EVs) in patients with LAM treated with mTOR inhibitor therapy (sirolimus or everolimus) compared with patients not receiving mTOR inhibitor therapy will be assessed using Electron Microscopy (EM).
One Year
Association between EVs characteristics and disease severity
Time Frame: One year
The concentration (particles/mL) and size (nanometers, nm) of extracellular vesicles (EVs) isolated from the plasma of patients with S-LAM, TSC-LAM, and TSC without pulmonary involvement will be analyzed for their association with disease severity, as assessed by the number of systemic manifestations of TSC and the presence of pulmonary disease.
One year
Association between EVs characteristics and pulmonary disease severity
Time Frame: One year
The concentration (particles/mL) and size (nanometers, nm) of extracellular vesicles (EVs) isolated from the plasma of patients with LAM (including both S-LAM and TSC-LAM) will be analyzed for their association with disease severity, based on the number of pulmonary complications, including pneumothoraces, chylothoraces, development of respiratory failure, and the need for lung transplantation.
One year
Association between EVs characteristics and pulmonary function
Time Frame: One year
The concentration (particles/mL) and size (nanometers, nm) of extracellular vesicles (EVs) isolated from the plasma of patients with LAM (including both S-LAM and TSC-LAM) will be analyzed for their association with pulmonary function, as measured by spirometry and diffusion parameters (FEV1, FVC, and DLCO), with FEV1 and FVC expressed in liters and % predicted, and DLCO expressed as % predicted.
One year

Collaborators and Investigators

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

Sponsor

University of Milan

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)

April 16, 2025

Primary Completion (Estimated)

January 16, 2026

Study Completion (Estimated)

August 20, 2026

Study Registration Dates

First Submitted

September 15, 2025

First Submitted That Met QC Criteria

December 12, 2025

First Posted (Actual)

December 26, 2025

Study Record Updates

Last Update Posted (Actual)

December 26, 2025

Last Update Submitted That Met QC Criteria

December 12, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LAM_EVs

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

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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