Autoantibody-associated autoimmune diseases (AAADs) are disorders in which dysfunctional plasma cells (PCs) secrete autoantibodies that attack healthy tissue. Many AAADs attack the nervous system, such as myasthenia gravis (MG), neuromyelitis optica, chronic inflammatory demyelinating polyneuropathy, Lambert- Eaton syndrome, and necrotizing autoimmune myopathy. This R44 (Clinical Trial Not Allowed) will support manufacturing of a new RNA-based cell therapy for neurological AAADs, and analysis of biomarkers from patients who received the therapy. Chimeric antigen receptor T cell (CAR-T) therapy eliminates pathogenic cells, such as PCs, by expressing engineered chimeric antigen receptors (CAR) in T cells isolated from a patient; the T cells are then reinfused to kill the CAR’s target. All approved CAR T drugs rely on gene transfer by DNA, which permanently modifies the genome. This poses several problems. DNA-modified CAR-T cells multiply exponentially because CAR DNA replicates; this can cause life-threatening inflammation called cytokine release syndrome (CRS). These CAR-T cells also require pre-treatment chemotherapy to create a niche for cell proliferation. DNA-modified CAR-T cells are expensive to make and use clinically, because frequent adverse events require close patient monitoring. These hurdles have limited CAR-T therapy only to advanced cancers. Cartesian Therapeutics has designed a new approach that replaces DNA with RNA to achieve transient, tunable CAR expression (rCAR-T). Unlike DNA-modified CAR T cells, CAR-encoding RNA cannot replicate and decays in predictable fashion. Thus, the patient’s exposure to rCAR-T cells is determined by cell dose. This avoids CRS and eliminates lymphodepleting chemotherapy. These advances create a versatile, clinically-validated means to treat neurological AAADs. We have developed an rCAR-T that targets B cell maturation antigen (BCMA). This marker is expressed on PCs – cells that produce autoantibodies in AAADs. This therapy – “Descartes-08” – transiently expresses anti-BCMA CAR to target BCMA+ PCs after infusion. MG is an AAAD in which BCMA+ PCs secrete autoantibodies that attack the neuromuscular junction, causing severe muscle weakness. In the first successful Phase 2a trial of a cell therapy to treat autoimmunity (NCT04146051), Descartes-08 conferred potent, safe, and long-lasting improvement in MG patients for 12 months or more, even though treatment was only 6-weeks (Lancet Neurology 2023). These benefits were achieved without the toxicity, inpatient stays, or lymphodepletion needed in DNA-based CAR-Ts. Here we propose key steps to develop rCAR-T as a new cell therapy option to treat neurological AAADs. The aims are i) manufacture Descartes-08 product lots to complete the Phase 2 MG clinical trial, ii) Identify clinical correlates in patient samples from ongoing randomized placebo-controlled trial (RCT) and iii) manufacture Descartes-08 lots for expanded access and basket trial patients with othe...