Adenine base editor–mediated correction of the common and severe IVS1-110 (G>A) β-thalassemia mutation

Author:

Hardouin Giulia123ORCID,Antoniou Panagiotis1ORCID,Martinucci Pierre1ORCID,Felix Tristan1ORCID,Manceau Sandra2,Joseph Laure24,Masson Cécile5ORCID,Scaramuzza Samantha6,Ferrari Giuliana67ORCID,Cavazzana Marina234ORCID,Miccio Annarita1ORCID

Affiliation:

1. 1Laboratory of Chromatin and Gene Regulation during Development, Imagine Institute, INSERM UMR1163, Paris Cité University, Paris, France

2. 2Biotherapy Clinical Investigation Center, Necker Children's Hospital, Assistance Publique Hopitaux de Paris, Paris, France

3. 3Human Lymphohematopoiesis Laboratory, Imagine Institute, INSERM UMR1163, Paris Cité University, Paris, France

4. 4Biotherapy Department, Necker Children's Hospital, Assistance Publique Hopitaux de Paris, Paris, France

5. 5Bioinformatics Platform, Imagine Institute, INSERM UMR1163, Paris Cité University, Paris, France

6. 6San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy

7. 7Vita-Salute San Raffaele University, Milan, Italy

Abstract

Abstractβ-Thalassemia (BT) is one of the most common genetic diseases worldwide and is caused by mutations affecting β-globin production. The only curative treatment is allogenic hematopoietic stem/progenitor cells (HSPCs) transplantation, an approach limited by compatible donor availability and immunological complications. Therefore, transplantation of autologous, genetically-modified HSPCs is an attractive therapeutic option. However, current gene therapy strategies based on the use of lentiviral vectors are not equally effective in all patients and CRISPR/Cas9 nuclease-based strategies raise safety concerns. Thus, base editing strategies aiming to correct the genetic defect in patients’ HSPCs could provide safe and effective treatment. Here, we developed a strategy to correct one of the most prevalent BT mutations (IVS1-110 [G>A]) using the SpRY-ABE8e base editor. RNA delivery of the base editing system was safe and led to ∼80% of gene correction in the HSPCs of patients with BT without causing dangerous double-strand DNA breaks. In HSPC-derived erythroid populations, this strategy was able to restore β-globin production and correct inefficient erythropoiesis typically observed in BT both in vitro and in vivo. In conclusion, this proof-of-concept study paves the way for the development of a safe and effective autologous gene therapy approach for BT.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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