PANORAMA: Neuromuscular Organoids for Refractory AChR+ Myasthenia Gravis

NCT07717281 | Recruiting DMC

• 1 other identifier: 6999
• Study Type: observational
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Myasthenia Gravis Generalized

Keywords

myasthenia gravis; neuromuscular organoids; end-plate dysfunction; biomarkers; regeneration strategies; refractory; anti-AChR antibodies

Outcome Measures

Primary Outcomes (1)

• Antibody-induced change in neuromuscular junction electrophysiological activity in a patient serum-derived organoid assay

  Change in spontaneous electrophysiological activity, measured as firing rate (Hz) by high-density multielectrode array (HD-MEA), in human neuromuscular organoids exposed to purified IgG from participants' serum. The primary comparison is between organoids exposed to IgG from treatment-refractory MG participants versus organoids exposed to IgG from treatment-sensitive MG, treatment-naive MG, and AChR-negative control participants, at the day 14 (chronic) exposure timepoint. The measure is assessed on a specimen-derived in vitro assay using participant-purified IgG, not on the participants directly. Lower firing rate indicates greater antibody-mediated neuromuscular junction dysfunction.

  Assessed in vitro at day 14 of organoid exposure to participant-derived IgG (chronic exposure timepoint)

Secondary Outcomes (4)

• Antibody-induced change in neuromuscular junction morphology in a patient serum-derived organoid assay

  Assessed in vitro at day 14 of organoid exposure to participant-derived IgG

• Validation of candidate refractoriness biomarkers in participants' serum

  Baseline

• Immunological profile across MG treatment-response subgroups

  Baseline

• Correlation between clinical severity, immunological profile, and organoid alterations

  Baseline

Study Arms (4)

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.

Eligibility Criteria

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

Study Population

Adults with acetylcholine receptor antibody-positive (AChR-positive) generalized myasthenia gravis, followed at two Italian tertiary referral centers for neuromuscular diseases, stratified by disease duration and response to conventional immunosuppressive therapy into treatment-naive, treatment-sensitive, and treatment-refractory subgroups. Both patients already followed at the participating centers (retrospective component) and newly evaluated patients (prospective component) are included. A control group of adults evaluated for neurological symptoms whose diagnostic work-up excluded neuromuscular disease is enrolled at the coordinating center only. Clinical data and residual (leftover) blood samples collected during routine clinical care are analyzed.

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead
• IRCCS Ospedale San Raffaele: collaborator

Study Sites (1)

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

RECRUITING

Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum, plasma, PBMCs (Peripheral Blood Mononuclear Cells)

MeSH Terms

Conditions

Myasthenia Gravis

Condition Hierarchy (Ancestors)

Paraneoplastic Syndromes, Nervous System; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Paraneoplastic Syndromes; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Neurodegenerative Diseases; Neuromuscular Junction Diseases; Neuromuscular Diseases; Autoimmune Diseases; Immune System Diseases

Central Study Contacts

Delia Gagliardi, MD, PhD

CONTACT

02 5503 3802; delia.gagliardi@policlinico.mi.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Neurologist

Study Record Dates

• First Submitted: July 13, 2026
• First Posted: July 21, 2026
• Study Start: June 4, 2026
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2028
• Last Updated: July 21, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)