First In human Successful CRISPR/Cas9 Gene Therapy (Exagamglogene Autotemcel) in a Heart Transplant Recipient with Beta-Thalassemia Major

Background/Introduction: Transfusion-dependent beta-thalassemia requires lifelong red blood cell transfusions, which can lead to severe iron overload and secondary hemochromatosis. Restrictive cardiomyopathy and end-stage heart failure are devastating, life-threatening complications of this iron toxicity. While gene editing therapies like exagamglogene autotemcel (Casgevy) offer a curative approach for thalassemia, they require myeloablative conditioning. Performing myeloablative conditioning and autologous stem cell transplantation in a solid organ transplant recipient on active immunosuppression presents unique immunological and physiological challenges. Consequently, a history of solid organ transplantation is frequently viewed as an absolute exclusion criterion for these advanced, curative cellular therapies.
Case Description: We report the first-in-human case of a 26-year-old male with beta-thalassemia major and severe hepatic iron overload (liver iron concentration of 20.6 mg/g dry weight) who developed restrictive cardiomyopathy and heart failure. He underwent two cycles of autologous PBSC collection in July and September 2024. On October 2024, he experienced refractory atrial fibrillation progressing to cardiac arrest, requiring resuscitation (ROSC) and initiation of ECMO. He subsequently required Impella placement and ultimately underwent an orthotopic heart transplant (OHT) that month. Post-transplant, he was maintained on immunosuppression including tacrolimus and mycophenolate mofetil.
Following cardiac rehabilitation, the patient was admitted for gene therapy to cure his underlying thalassemia and prevent future iron toxicity to the allograft. He underwent myeloablative conditioning in Aug  2025 with intravenous Busulfan from Day -7 to Day -4, dynamically adjusted to a target AUC of 900 micromol-min/L via pharmacokinetic monitoring. On Day 0 he received an infusion of Casgevy (exagamglogene autotemcel) at a dose of 4.0 x 10^6 CD34+ cells/kg.
Results: Demonstrating the clinical feasibility of this complex approach, the patient safely tolerated myeloablative conditioning and cellular infusion while continuing his post-transplant tacrolimus regimen, but holding MMF, with no evidence of allograft rejection. Neutrophil engraftment was achieved on Day +25, and platelet engraftment occurred on Day +48. He rapidly achieved transfusion independence, with his last packed red blood cell (PRBC) transfusion on September 2025. At his Day +128 discharge clinic visit, the patient reported high energy levels and excellent functional status. Laboratory results demonstrated a total hemoglobin of 9.3 g/dL with a robust fetal hemoglobin (HbF) fraction of 87.6%. His cardiac allograft function remained stable with a preserved left ventricular ejection fraction (LVEF) of 57% on echocardiogram.He is now 7 months post Gene therapy an ddoingw el  withour graft rejection of his allo-heart and remains trasfsuion independent. 
Conclusion: This first-in-human case establishes the feasibility and safety of administering myeloablative CRISPR/Cas9-edited gene therapy in a highly immunosuppressed, recent heart transplant recipient. Curing the underlying beta-thalassemia and achieving transfusion independence definitively eliminates the primary source of iron overload, thereby protecting the cardiac allograft. Crucially, this success highlights that a history of solid organ transplantation and concurrent immunosuppression should no longer serve as exclusion criteria, paving the way for future patients with severe hemoglobinopathies to access life-saving gene therapies.