Editas, a company founded by Zhang Feng, initiates a clinical trial of CRISPR-Cas12a gene editing for the treatment of β-thalassemia

Written | Edited by Wang Cong | Typesetting by Wang Duoyu | Shui Chengwen Thalassemia is a single-gene genetic disease with the widest distribution and the largest number of people in the world.
It is also the genetic disease with the greatest impact and the highest incidence in China.
There are 30 million thalassemia gene carriers.
Thalassemia is rare in northern China, but it is more common in Guangdong, Guangxi, Sichuan and other places, especially in Guangdong.
On average, 1 out of every 9 Guangdong people carries thalassemia caused by thalassemia.
disease genes
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There are many types of thalassemia, of which β-thalassemia is the most common and severe type, which is caused by mutations in genes that express β-globin
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β-thalassemia can be divided into transfusion-dependent (TDT) and non-transfusion-dependent (NTDT).
Patients with transfusion-dependent thalassemia require life-long regular blood transfusions to prevent organ failure and death.
Iron overload caused by long-term blood transfusions can lead to multiple Organ dysfunction and failure
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In human cells, γ-globin has a similar function to β-globin, and γ-globin is silenced and no longer expressed in human adulthood.
If the expression of the γ-globin gene in patients with β-thalassemia can be reactivated , can make up for the lack of β-globin, thereby relieving or curing β-thalassemia
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In addition, sickle cell disease is also caused by mutations in the gene that expresses beta-globin, and therefore, also applies to this therapeutic idea
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Beta-thalassemia and sickle cell disease are both caused by mutations in the gene that expresses beta-globin, which has previously been found to function similarly to beta-globin, which in adult humans Then it will be silent and no longer express
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Therefore, if the expression of the γ-globin gene can be reactivated, the loss of β-globin can be compensated, thereby alleviating or curing these two inherited anemias
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Recently, Editas Medicine, founded by Professor Feng Zhang, one of the founders of CRISPR gene editing, announced that its IND application for EDIT-301, a gene editing therapy for the treatment of transfusion-dependent beta-thalassemia, has been approved by the FDA and will be launched in 20221 /Phase 2 clinical trial to evaluate the safety, tolerability and preliminary efficacy of EDIT-301 in the treatment of transfusion-dependent beta-thalassemia
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Preclinical studies have shown that EDIT-301 therapy can significantly increase red blood cell gamma-globin levels and total hemoglobin levels, significantly improve red blood cell maturation and reduce red blood cell death, making it an effective treatment option
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The therapy is modified at the DNA level, so one treatment can be effective for life
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Therapeutic Principle Therapeutic Principle EDIT-301 is a CRISPR gene-editing therapy under development by Editas Medicine for the treatment of sickle cell disease and beta-thalassemia
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The therapy does not use the well-known CRISPR-Cas9 gene editing system, but the CRISPR-Cas12a gene editing system developed by Zhang Feng
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Specifically, this gene editing therapy is to perform gene editing on patient-derived CD34+ hematopoietic stem and progenitor cells.
The editing site is the promoter region of the HBG gene, because the promoter region of the HBG gene is the binding of the transcriptional repressor BCL11A.
At the site, targeting the site can inhibit BCL11A, thereby reactivating the expression of γ-globin and improving the patient's erythrocyte maturation
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The therapy uses an RNP (RNA and protein complex) composed of Cas12a and gRNA, which is then transfected into cells by electroporation to avoid the risk of random insertion with viral vectors
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The therapy can also treat sickle cell disease, and Editas Medicine has started a clinical trial of the therapy for sickle cell anemia under clinical trial number NCT04853576
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CRISPR-Cas12aCRISPR-Cas12a is a new CRISPR gene editing tool developed by Zhang Feng's team in 2015.
The paper was published in the journal Cell.
It was originally named CRISPR-Cpf1, and then changed to CRISPR-Cas12a
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CRISPR-Cas12a is similar to CRISPR-Cas9, but there are differences in DNA targeting and editing mechanisms.
Cas12a requires a different PAM sequence than Cas9, so it can target unique DNA sequences in the genome.
The cleavage of DNA double-strands results in staggered nicks, which can improve the efficiency and accuracy of certain gene repair methods
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These differences make CRISPR-Cas12a and Cas9 complementary to a certain extent, broadening the application scope of CRISPR gene editing
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Image source: Editas Medicine official website Editas Medicine R&D pipeline Introduction Editas Medicine's current R&D pipeline is divided into three major parts, namely in vivo gene editing therapy, in vitro gene editing therapy and cell therapy
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There are 4 pipelines of in vivo gene editing therapy, the fastest progress is EDIT-101, the CRISPR-Cas9 gene editing system delivered by AAV vector for the treatment of congenital amaurosis type 10 (LCA10)
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The other 3 have not yet started clinical trials
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On September 29, 2021, Editas Medicine presented preliminary positive clinical trial results from the Phase 1/2 clinical trial of EDIT-101 at the 19th International Symposium on Retinal Degeneration (RD2021)
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No serious adverse events or dose-limiting toxicities were observed, and the therapeutic effect shown in the middle-dose group provided preliminary support for clinical benefit.
Editas said that the treatment of the adult high-dose group (3 × 10E12vg/ml) will be continued and will be carried out Treatment of the middle-dose group (1.
1×10E12vg/ml) in children
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There are 2 pipelines of in vitro gene editing therapy, using CRISPR-Cas2a to edit patient-derived CD34+ hematopoietic stem and progenitor cells in vitro for the treatment of sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT)
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The former has started clinical trials, and the latter has passed the FDA's IND application and is about to start clinical trials
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There are 2 pipelines of cell therapy, gene editing of αβ T cells (developed in cooperation with BMS) and iPSC NK cells (developed in cooperation with BlueRock) for tumor treatment
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References: https://ir.
editasmedicine.
com/news-releases/news-release-details/editas-medicine-announces-fda-clearance-investigational-new-drug https:// -pipeline/open reprint welcome to forward to the circle of friends and WeChat group