PANORAMA: Neuromuscular Organoids for Refractory AChR+ Myasthenia Gravis | NCT07717281

NCT07717281

Overview

NCT ID: NCT07717281
Lead Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoOTHER
Official Title: From PAtients to Neuromuscular Organoids in Refractory AChR+ Myasthenia grAvis: End-plate Dysfunction, Biomarker Discovery and Regeneration Strategies
Brief Summary: Myasthenia gravis (MG) is an autoimmune disease in which autoantibodies attack the neuromuscular junction, the site at which nerve cells communicate with muscle fibres, impairing signal transmission and causing fluctuating muscle weakness that worsens with sustained activity. In most patients this dysfunction is reversible and improves with treatments that suppress the immune response. About 10 to 15 percent of patients do not respond adequately to standard therapy, and the mechanisms of this refractory course remain unclear.

The study is based on the hypothesis that in refractory patients the autoantibody attack causes irreversible damage to the neuromuscular junction, and that this damage sustains symptoms despite appropriate treatment. A further aim is to identify circulating biomarkers reflecting such damage that may help predict response to therapy.

The study includes adults with generalised MG positive for antibodies against the acetylcholine receptor, stratified by disease duration and treatment response into treatment-naive, treatment-sensitive and treatment-refractory MG. Subjects without neuromuscular disease and negative for these antibodies serve as controls. Blood samples (serum, plasma and mononuclear cells) are obtained from material left over from blood draws performed as part of routine care, together with clinical data including disease duration, symptom severity measured with validated scales (MG-ADL and QMG), antibody titre and treatment history. No study-specific visit or blood draw is required.

Antibodies purified from participants are applied to human neuromuscular organoids, three-dimensional models grown from stem cells of healthy donors that reproduce key features of the neuromuscular junction. Exposing these organoids to antibodies from patients at different disease stages reproduces the antibody-mediated attack under controlled laboratory conditions and allows the resulting structural and electrical changes to be measured. Molecules released by damaged organoids, including microRNAs and proteins, are identified and then measured in participants' blood. The immune profile of participants, including complement factors, lymphocyte subsets and cytokines, is characterised in parallel.

The study will determine whether irreversible neuromuscular junction damage distinguishes treatment-refractory MG from treatment-responsive disease, and whether specific circulating biomarkers can identify a refractory course.

Status and Timeline

Status: Recruiting
Last Update Posted: Jul 21, 2026Actual
Start Date: Jun 4, 2026Actual
Primary Completion Date: Mar 31, 2028Estimated
Completion Date

Participation Criteria

Ages Eligible for Study: Adult (18-64)Older Adult (65+)
Sexes Eligible for Study: All
Accepts Healthy Volunteers?: Yes
Eligibility Criteria: Inclusion Criteria:

AChR-positive MG participants (all of the following):

Age >= 18 years

Established diagnosis of myasthenia gravis according to international criteria (fluctuating muscle weakness plus at least one of: positive anticholinesterase test; >10% decrement on repetitive nerve stimulation [SR-ENG]; or increased jitter on single-fiber EMG [SFEMG])

Anti-AChR antibody positivity confirmed by serological testing

Generalized MG stratified by disease duration and response to conventional immunosuppressive therapy into: treatment-naive MG (nMG); treatment-sensitive MG with stable disease and at least 12 months of follow-up (sMG); or treatment-refractory MG with at least 12 months of follow-up (rMG)

Signed informed consent (prospective component)

For the retrospective component, availability of biobanked biological samples with a signed specific informed consent

Control participants (all of the following):

Age >= 18 years

Absence of neuromuscular disease

Absence of known autoimmune disease

No ongoing immunosuppressive or immunomodulatory therapy

Negative for anti-AChR and anti-MuSK antibodies

Age- and sex-matched to the MG groups

Signed informed consent

Exclusion Criteria:

Seronegative (AChR-negative) generalized MG, or MG with anti-MuSK or other non-AChR antibodies

Purely ocular myasthenia gravis

Other concomitant neuromuscular disease (e.g., Lambert-Eaton myasthenic syndrome, polymyositis, muscular dystrophies)

Pregnancy or breastfeeding

Inability to provide informed consent

Study Plan

Study Type: Observational
Phase: No data available
Enrollment: 40Estimated
Primary Purpose: No data available
Allocation: No data available
Interventional Model: No data available
Masking: No data available

Contacts and Locations

Central Contacts: Delia Gagliardi, MD, PhDContact
delia.gagliardi@policlinico.mi.it02 5503 3802 ext. +39

Similar Studies

Participant Group/Arms

Treatment-naive AChR-positive generalized MG (nMG)

Adults with acetylcholine receptor antibody-positive (AChR-positive) generalized myasthenia gravis with a recent diagnosis who have not yet started immunosuppressive therapy. Clinical data (disease duration, MGFA class, MG-ADL and QMG scores, antibody titers, treatment history) and residual (leftover) blood samples (serum, plasma, PBMC) collected during routine clinical care are analyzed. No study-specific intervention or extra blood draw is performed. Purified IgG from these participants is applied in vitro to human neuromuscular organoids to model antibody-mediated neuromuscular junction damage, and candidate circulating biomarkers (microRNAs, proteins) identified in the organoid models are validated in the participants' serum.

Treatment-sensitive AChR-positive generalized MG (sMG)

Adults with AChR-positive generalized myasthenia gravis who respond to conventional immunosuppressive therapy and have stable disease, with at least 12 months of follow-up. Clinical data (disease duration, MGFA class, MG-ADL and QMG scores, antibody titers, treatment history) and residual (leftover) blood samples (serum, plasma, PBMC) collected during routine clinical care are analyzed. No study-specific intervention or extra blood draw is performed. Purified IgG from these participants is applied in vitro to human neuromuscular organoids to model antibody-mediated neuromuscular junction damage, and candidate circulating biomarkers (microRNAs, proteins) identified in the organoid models are validated in the participants' serum.

Treatment-refractory AChR-positive generalized MG (rMG)

Adults with AChR-positive generalized myasthenia gravis who do not respond to appropriate conventional immunosuppressive therapy, with at least 12 months of follow-up and poor disease control. Clinical data (disease duration, MGFA class, MG-ADL and QMG scores, antibody titers, treatment history) and residual (leftover) blood samples (serum, plasma, PBMC) collected during routine clinical care are analyzed. No study-specific intervention or extra blood draw is performed. Purified IgG from these participants is applied in vitro to human neuromuscular organoids to model antibody-mediated neuromuscular junction damage, and candidate circulating biomarkers (microRNAs, proteins) identified in the organoid models are validated in the participants' serum.

Non-neuromuscular, AChR-negative controls

Adults without neuromuscular disease and negative for anti-AChR and anti-MuSK antibodies, age- and sex-matched to the MG groups and free of known autoimmune disease and ongoing immunosuppressive or immunomodulatory therapy. They are assessed for neurological symptoms with a diagnostic work-up that excludes neuromuscular disease. Demographic data and residual (leftover) blood samples (serum, plasma, PBMC) collected during routine clinical care are analyzed. No study-specific intervention or extra blood draw is performed. AChR-negative serum from these participants serves as the negative control in the in vitro human neuromuscular organoid experiments and as the reference group for immunological and biomarker comparisons.