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Written | Edited by Wang Cong | Wang Duoyu Typesetting | Hydrogenous thalassemia is a single-gene genetic disease with the most widespread 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.
It is only available 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 Cantonese has carried thalassemia.
Disease gene
.
There are many types of thalassemia, among which β-thalassemia is the most common and most serious type.
It is caused by mutations in genes expressing β-globin
.
Beta-thalassemia can be divided into transfusion-dependent (TDT) and non-transfusion-dependent (NTDT).
Patients with transfusion-dependent thalassemia need regular blood transfusions throughout their lives to prevent organ failure and death, and iron overload caused by long-term blood transfusion can cause multiple Organ dysfunction and failure
.
In human cells, γ-globin and β-globin function similarly, and γ-globin will be silent and no longer expressed after adulthood.
If it can reactivate the expression of γ-globin gene in patients with β-thalassemia , Can make up for the lack of β-globin, thereby alleviating or curing β-thalassemia
.
In addition, sickle cell disease is also caused by mutations in the gene that expresses β-globin, so it is also suitable for this kind of treatment
.
Both β-thalassemia and sickle cell disease are caused by mutations in the gene expressing β-globin.
Previous studies have found that γ-globin has similar functions to β-globin, and γ-globin is found in human adults.
Then there will be silence and no more expression
.
Therefore, if the expression of γ-globin gene can be reactivated, it can make up for the lack of β-globin, thereby alleviating or curing these two hereditary anemias.
.
Recently, Editas Medicine, founded by Professor Zhang Feng, one of the founders of CRISPR gene editing, announced that its IND application for the gene editing therapy EDIT-301 for the treatment of transfusion-dependent β-thalassemia has been approved by the FDA and will be launched in 20221 The Phase 2 clinical trial aims to evaluate the safety, tolerability and preliminary efficacy of EDIT-301 in the treatment of transfusion-dependent β-thalassemia
.
Preclinical studies have shown that EDIT-301 therapy can significantly increase the γ-globin level and total hemoglobin level in red blood cells, significantly improve red blood cell maturation and reduce red blood cell death, so it can be used as an effective treatment option
.
The therapy is a modification at the DNA level, so it can be effective for a lifetime
.
Therapeutic principle Therapeutic principle EDIT-301 is a CRISPR gene editing therapy for sickle cell disease and β-thalassemia being developed by Editas Medicine
.
The therapy does not use the well-known CRISPR-Cas9 gene editing system, but the CRISPR-Cas12a gene editing system developed by Feng Zhang
.
Specifically, the gene editing therapy is to perform gene editing on CD34+ hematopoietic stem cells and progenitor cells from the patient.
The editing site is the promoter region of the HBG gene.
This is because the promoter region of the HBG gene is a combination of the transcription repressor BCL11A To the site, changing the target to a site can inhibit BCL11A, thereby reactivating the expression of γ-globin and improving the patient's red blood cell maturation
.
The therapy uses RNP (RNA and protein complex) composed of Cas12a and gRNA, which is then transfected into cells by electroporation technology to avoid the risk of random insertion caused by the use of viral vectors
.
This therapy can also treat sickle cell disease, and Editas Medicine has started a clinical trial of this therapy for sickle cell anemia, the clinical trial number is NCT04853576
.
CRISPR-Cas12a CRISPR-Cas12a is a new CRISPR gene editing tool developed by Feng Zhang's team in 2015.
The paper was published in the Cell journal, originally named CRISPR-Cpf1, and later changed to CRISPR-Cas12a
.
CRISPR-Cas12a is similar to CRISPR-Cas9, but the two have differences in DNA targeting and editing mechanisms.
The PAM sequence required by Cas12a is different from that of Cas9, so it can target unique DNA sequences in the genome.
In addition, Cas12a pairs The cleavage of the double strands of DNA results in staggered nicks, which can improve the efficiency and accuracy of certain gene repair methods
.
These differences make CRISPR-Cas12a and Cas9 complement each other to a certain extent, broadening the application range of CRISPR gene editing
.
Image source: Editas Medicine official website Editas Medicine R&D pipeline introduction Editas Medicine's current R&D pipeline is divided into three parts, namely in vivo gene editing therapy, in vitro gene editing therapy and cell therapy
.
There are 4 pipelines for in vivo gene editing therapy.
The fastest progressing is EDIT-101, the CRISPR-Cas9 gene editing system delivered by AAV vector to treat congenital amaurosis type 10 (LCA10)
.
The other three have not yet started clinical trials
.
On September 29, 2021, Editas Medicine released the preliminary positive clinical trial results of the Phase 1/2 clinical trial of EDIT-101 at the 19th International Symposium on Retinal Degeneration (RD2021)
.
No serious adverse events or dose-limiting toxicity were observed.
The therapeutic effect shown in the middle-dose group provided preliminary support for the clinical benefit.
Editas stated that it will continue the treatment of the adult high-dose group (3×10E12vg/ml) and will carry out The treatment of children's middle dose group (1.
1×10E12vg/ml)
.
There are two pipelines for in vitro gene editing therapy, using CRISPR-Cas2a to edit patient-derived CD34+ hematopoietic stem and progenitor cells in vitro to treat sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT)
.
The former has started clinical trials, and the latter has passed the FDA's IND application, and clinical trials are about to start
.
There are two pipelines for 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
.
Reference: https://ir.
editasmedicine.
com/news-releases/news-release-details/editas-medicine-announces-fda-clearance-investigational-new-drughttps:// -pipeline/open reprint, welcome to forward to the circle of friends and WeChat group
It is also the genetic disease with the greatest impact and the highest incidence in China.
It is only available 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 Cantonese has carried thalassemia.
Disease gene
.
There are many types of thalassemia, among which β-thalassemia is the most common and most serious type.
It is caused by mutations in genes expressing β-globin
.
Beta-thalassemia can be divided into transfusion-dependent (TDT) and non-transfusion-dependent (NTDT).
Patients with transfusion-dependent thalassemia need regular blood transfusions throughout their lives to prevent organ failure and death, and iron overload caused by long-term blood transfusion can cause multiple Organ dysfunction and failure
.
In human cells, γ-globin and β-globin function similarly, and γ-globin will be silent and no longer expressed after adulthood.
If it can reactivate the expression of γ-globin gene in patients with β-thalassemia , Can make up for the lack of β-globin, thereby alleviating or curing β-thalassemia
.
In addition, sickle cell disease is also caused by mutations in the gene that expresses β-globin, so it is also suitable for this kind of treatment
.
Both β-thalassemia and sickle cell disease are caused by mutations in the gene expressing β-globin.
Previous studies have found that γ-globin has similar functions to β-globin, and γ-globin is found in human adults.
Then there will be silence and no more expression
.
Therefore, if the expression of γ-globin gene can be reactivated, it can make up for the lack of β-globin, thereby alleviating or curing these two hereditary anemias.
.
Recently, Editas Medicine, founded by Professor Zhang Feng, one of the founders of CRISPR gene editing, announced that its IND application for the gene editing therapy EDIT-301 for the treatment of transfusion-dependent β-thalassemia has been approved by the FDA and will be launched in 20221 The Phase 2 clinical trial aims to evaluate the safety, tolerability and preliminary efficacy of EDIT-301 in the treatment of transfusion-dependent β-thalassemia
.
Preclinical studies have shown that EDIT-301 therapy can significantly increase the γ-globin level and total hemoglobin level in red blood cells, significantly improve red blood cell maturation and reduce red blood cell death, so it can be used as an effective treatment option
.
The therapy is a modification at the DNA level, so it can be effective for a lifetime
.
Therapeutic principle Therapeutic principle EDIT-301 is a CRISPR gene editing therapy for sickle cell disease and β-thalassemia being developed by Editas Medicine
.
The therapy does not use the well-known CRISPR-Cas9 gene editing system, but the CRISPR-Cas12a gene editing system developed by Feng Zhang
.
Specifically, the gene editing therapy is to perform gene editing on CD34+ hematopoietic stem cells and progenitor cells from the patient.
The editing site is the promoter region of the HBG gene.
This is because the promoter region of the HBG gene is a combination of the transcription repressor BCL11A To the site, changing the target to a site can inhibit BCL11A, thereby reactivating the expression of γ-globin and improving the patient's red blood cell maturation
.
The therapy uses RNP (RNA and protein complex) composed of Cas12a and gRNA, which is then transfected into cells by electroporation technology to avoid the risk of random insertion caused by the use of viral vectors
.
This therapy can also treat sickle cell disease, and Editas Medicine has started a clinical trial of this therapy for sickle cell anemia, the clinical trial number is NCT04853576
.
CRISPR-Cas12a CRISPR-Cas12a is a new CRISPR gene editing tool developed by Feng Zhang's team in 2015.
The paper was published in the Cell journal, originally named CRISPR-Cpf1, and later changed to CRISPR-Cas12a
.
CRISPR-Cas12a is similar to CRISPR-Cas9, but the two have differences in DNA targeting and editing mechanisms.
The PAM sequence required by Cas12a is different from that of Cas9, so it can target unique DNA sequences in the genome.
In addition, Cas12a pairs The cleavage of the double strands of DNA results in staggered nicks, which can improve the efficiency and accuracy of certain gene repair methods
.
These differences make CRISPR-Cas12a and Cas9 complement each other to a certain extent, broadening the application range of CRISPR gene editing
.
Image source: Editas Medicine official website Editas Medicine R&D pipeline introduction Editas Medicine's current R&D pipeline is divided into three parts, namely in vivo gene editing therapy, in vitro gene editing therapy and cell therapy
.
There are 4 pipelines for in vivo gene editing therapy.
The fastest progressing is EDIT-101, the CRISPR-Cas9 gene editing system delivered by AAV vector to treat congenital amaurosis type 10 (LCA10)
.
The other three have not yet started clinical trials
.
On September 29, 2021, Editas Medicine released the preliminary positive clinical trial results of the Phase 1/2 clinical trial of EDIT-101 at the 19th International Symposium on Retinal Degeneration (RD2021)
.
No serious adverse events or dose-limiting toxicity were observed.
The therapeutic effect shown in the middle-dose group provided preliminary support for the clinical benefit.
Editas stated that it will continue the treatment of the adult high-dose group (3×10E12vg/ml) and will carry out The treatment of children's middle dose group (1.
1×10E12vg/ml)
.
There are two pipelines for in vitro gene editing therapy, using CRISPR-Cas2a to edit patient-derived CD34+ hematopoietic stem and progenitor cells in vitro to treat sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT)
.
The former has started clinical trials, and the latter has passed the FDA's IND application, and clinical trials are about to start
.
There are two pipelines for 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
.
Reference: https://ir.
editasmedicine.
com/news-releases/news-release-details/editas-medicine-announces-fda-clearance-investigational-new-drughttps:// -pipeline/open reprint, welcome to forward to the circle of friends and WeChat group
