更新于：2024-11-01

核酸酶Cas9 x β-globin

更新于：2024-11-01

基本信息

关联

项与核酸酶Cas9 x β-globin 相关的药物

CRISPR-SCD-001

靶点

核酸酶Cas9 x β-globin

作用机制

HBB基因刺激剂 [+1]

在研机构

University of California, Los Angeles

原研机构

University of California, Los Angeles

在研适应症

终末期肾脏病 [+1]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

100 项与核酸酶Cas9 x β-globin 相关的临床结果

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100 项与核酸酶Cas9 x β-globin 相关的转化医学

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0 项与核酸酶Cas9 x β-globin 相关的专利（医药）

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项与核酸酶Cas9 x β-globin 相关的文献（医药）

2021-04-01·Cell Reports Medicine

Preclinical evaluation for engraftment of CD34+ cells gene-edited at the sickle cell disease locus in xenograft mouse and non-human primate models

Article

作者: Demirci, Selami ; Bonifacino, Aylin C ; Krouse, Allen E ; Nassehi, Tina ; Haro-Mora, Juan J ; Allen, Cornell ; Tisdale, John F ; De Ravin, Suk See ; Leonard, Alexis ; Drysdale, Claire M ; Linde, N Seth ; Donahue, Robert E ; Uchida, Naoya ; Yapundich, Morgan ; Li, Linhong ; Malech, Harry L ; Gamer, Jackson ; Peshwa, Madhusudan V

Sickle cell disease (SCD) is caused by a 20A > T mutation in the β-globin gene. Genome-editing technologies have the potential to correct the SCD mutation in hematopoietic stem cells (HSCs), producing adult hemoglobin while simultaneously eliminating sickle hemoglobin. Here, we developed high-efficiency viral vector-free non-footprint gene correction in SCD CD34⁺ cells with electroporation to deliver SCD mutation-targeting guide RNA, Cas9 endonuclease, and 100-mer single-strand donor DNA encoding intact β-globin sequence, achieving therapeutic-level gene correction at DNA (∼30%) and protein (∼80%) levels. Gene-edited SCD CD34⁺ cells contributed corrected cells 6 months post-xenograft mouse transplant without off-target δ-globin editing. We then developed a rhesus β-to-βs-globin gene conversion strategy to model HSC-targeted genome editing for SCD and demonstrate the engraftment of gene-edited CD34⁺ cells 10-12 months post-transplant in rhesus macaques. In summary, gene-corrected CD34⁺ HSCs are engraftable in xenograft mice and non-human primates. These findings are helpful in designing HSC-targeted gene correction trials.

2019-12-05·Nature1区 · 综合性期刊

Search-and-replace genome editing without double-strand breaks or donor DNA

1区 · 综合性期刊

Article

作者: Davis, Jessie R ; Koblan, Luke W ; Sousa, Alexander A ; Randolph, Peyton B ; Anzalone, Andrew V ; Liu, David R ; Levy, Jonathan M ; Wilson, Christopher ; Newby, Gregory A ; Chen, Peter J ; Raguram, Aditya

Most genetic variants that contribute to disease¹ are challenging to correct efficiently and without excess byproducts^2-5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 edits in human cells, including targeted insertions, deletions, and all 12 types of point mutation, without requiring double-strand breaks or donor DNA templates. We used prime editing in human cells to correct, efficiently and with few byproducts, the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay-Sachs disease (requiring a deletion in HEXA); to install a protective transversion in PRNP; and to insert various tags and epitopes precisely into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, has complementary strengths and weaknesses compared to base editing, and induces much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases.