PANORAMA: Neuromuscular Organoids for Refractory AChR+ Myasthenia Gravis

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.

Eligibility

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

Conditions2

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