公开(公告)号：US20240318154A1

公开(公告)日：2024-09-26

申请号：US18561938

申请日：2022-05-20

申请人： CELLECTIS ,  Albert-Ludwigs-Universitat Freiburg

发明人： Toni CATHOMEN ,  Tatjana CORNU ,  Julia KLERMUND ,  Manuel RHIEL ,  Julia ROSITZKA ,  Philippe DUCHATEAU ,  Alexandre JUILLERAT

IPC分类号： C12N9/22 ,  A61K35/28 ,  C07K14/47 ,  C12N5/0789 ,  C12N15/90

CPC分类号： C12N9/22 ,  A61K35/28 ,  C07K14/4705 ,  C12N5/0647 ,  C12N15/907 ,  C12N2510/00

摘要： The present invention generally relates to the field of genome engineering (gene editing), and more specifically to gene therapy for the treatment of Severe Combined Immunodeficiency (SCID) related to RAG1. Particularly, the present invention pertains to the treatment of RAG1 deficiency in long-term repopulating hematopoietic stem cells (HSCs). The present invention provides means and methods for genetically modifying HSCs involving gene editing reagents, such as TALE-nucleases, that specifically target a non-functional endogenous RAG1 gene, comprising at least one mutation causing Severe Combined Immunodeficiency (SCID), thereby allowing the restoration of the normal cellular phenotype. The present invention also provides engineered RAG1-edited HSCs comprising an exogenous sequence comprising a nucleic acid sequence encoding a functional RAG1 protein which is integrated in said HSCs' genome into a non-functional RAG1 endogenous locus, resulting in the expression of a functional RAG1 polypeptide. The present invention further provides populations of cells comprising said engineered HSCs, pharmaceutical compositions comprising said engineered HSCs or populations of cells, as well as their use in gene therapy for the treatment of Severe Combined Immunodeficiency (SCID) related to RAG1.