Project description:β-thalassemia is a highly prevalent monogenic recessive disease caused by mutations affecting the synthesis of the adult hemoglobin β-chains. Transplantation of autologous, genetically modified hematopoietic stem/progenitor cells (HSPCs) is an attractive therapeutic option. However, current gene therapy strategies based on the use of lentiviral vectors or CRISPR/Cas9 nuclease are not equally effective in all the patients and/or raise safety concerns. Base editing (BE), a new CRISPR/Cas9 derived genome editing tool, allows the effective introduction of point mutations at precise locations within the genome without generating double strand breaks. The two β0 mutations CD39 (CAG>TAG) and IVS2-1 (G>A) are among the most common and severe β-thalassemia mutations in the Mediterranean area and Middle East. We exploited the capacity of BE to correct these mutations in HSPCs from β-thalassemia patients. We demonstrated that red blood cells in vitro derived from edited HSPCs exhibited high β-globin levels and that the delayed erythroid differentiation typically observed in β-thalassemic cell cultures was corrected by our treatment. Finally, xenotransplantation experiments showed base editing in HSCs and correction of the β-thalassemic phenotype in vivo. Overall, our study provides in vitro and in vivo proof of efficacy of a BE approach to treat patients with prevalent and severe β-thalassemia mutations.

2025-05-05 | GSE273814 | GEO

Base editing mediated correction of severe β0 IVS2-1 thalassemia mutations.

2025-05-05 | GSE292238 | GEO

Base editing mediated correction of severe β0 IVS2-1 thalassemia mutations.

Project description:Base editing mediated correction of severe β0 IVS2-1 thalassemia mutations.

| PRJNA1237708 | ENA

Naïve iPSCs Generated from β-thalassemia Fibroblasts Allow Efficient Gene Correction with CRISPR/Cas9

Project description:We used a modified 5i/L/FA system to generate transgene-free naïve iPSCs directly from the fibroblasts of a patient suffering from β-thalassemia and further demonstrated efficient gene correction with a CRISPR/Cas9 system, which provides an improved strategy for personalized treatment of β-thalassemia.

2016-12-01 | GSE69319 | GEO

Therapeutic base editing alleviates restrictive cardiomyopathy

Project description:Restrictive cardiomyopathy (RCM) is a severe cardiac disorder characterized by impaired ventricular filling and diastolic dysfunction, with mutations in sarcomeric proteins representing major causative factors. Mutations of TNNI3 gene (e.g. p.R192H) constitute major genetic causes of RCM, particularly affecting pediatric patients and being associated with poor prognosis. Here, we demonstrate that adenine base editor (ABE) is able effectively correct RCM-causing mutation and alleviate RCM in a murine model. We first developed a novel murine model harboring the Tnni3R193H mutation that recapitulates the hallmark features of human RCM. Importantly, targeted delivery of ABE via adeno-associated virus (AAV) achieved efficient and precise correction of the Tnni3R193H mutation in adult RCM mice, leading to significant improvement of cardiac functions. Our findings establish base editing as a therapeutic strategy for RCM and highlight its broader potential for treating genetic cardiomyopathies in clinical settings.

2025-04-30 | GSE295799 | GEO

Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy

Project description:Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy

| PRJNA938798 | ENA

Direct correction of haemoglobin E / beta-thalassaemia using base editors

Project description:Direct correction of haemoglobin E / beta-thalassaemia using base editors

| PRJNA849199 | ENA