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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, and interested parties.
Long press or scan the QR code below to follow us.
iNature sickle cell disease is an autosomal recessive genetic disease caused by mutations in HBB, usually encoding adult β-globin (βA).
Although allogeneic hematopoietic stem cell (HSC) transplantation can cure SCD, it is usually not possible to obtain the best matched donor, and the procedure may result in transplant rejection or graft-versus-host disease.
On June 2, 2021, David R.
Liu (Liu Ruqian) of the Broad Institute and other teams published a research paper titled "Base editing of haematopoietic stem cells rescues sickle cell disease in mice" in Nature online, which used a customized gland The purine base editor (ABE8e-NRCH) converts the SCD allele (HBBS) to Makassar β-globin (HBBG), which is a non-pathogenic variant.
The delivery of mRNA encoding the base editor and targeting guide RNA in vitro to the hematopoietic stem and progenitor cells (HSPC) of SCD patients resulted in the conversion of 80% of HBBS to HBBG.
After 16 weeks of transplanting edited human HSPC into immunodeficient mice, the frequency of HBBG was 68%, and hypoxia-induced bone marrow reticulocyte sickle cells decreased by 5 times, indicating that gene editing is durable.
In order to evaluate the physiological effects of HBBS base editing, the study provided ABE8e-NRCH and introduced RNA from humanized SCD mice into HSPC, and then transplanted these cells into irradiated mice.
Sixteen weeks later, Makassar β-globin accounted for 79% of the β-globin in the blood, and sickle cells caused by hypoxia were reduced by three times.
Compared with mice that received unedited cells, mice that received base-edited HSPC showed near-normal hematological parameters and reduced splenic pathology.
The second transplantation of edited bone marrow confirmed that gene editing is durable in long-term hematopoietic stem cells and showed that 20% or more HBBS-to-HBBG editing is sufficient for phenotypic rescue.
The base editing of human HSPC avoids the p53 activation and larger deletions observed after Cas9 nuclease treatment.
In summary, these findings indicate that a one-time autotherapy of SCD can eliminate pathogenic HBBS, produce benign HBBG, and minimize the adverse consequences of double-stranded DNA breaks.
In addition, on February 19, 2021, David R.
Liu from the Broad Institute and Dong Min from Harvard Medical School jointly published a research paper entitled "Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity" in Science Online.
This research developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light chain proteases.
The research evolved BoNT/X protease into separate variants, which preferentially cleave vesicle-associated membrane protein 4 (VAMP4) and Ykt6, and evolved BoNT/F protease to selectively cleave the unnatural substrate VAMP7, and evolved BoNT/E protease cleaves phosphatase and tendon homologous protein (PTEN), but is not any natural BoNT protease substrate in neurons.
The evolved proteases show large changes in specificity (218-fold to 11,000,000-fold) and can retain their ability to form holotoxins that are self-delivered to primary neurons.
These findings establish a universal platform for reprogramming proteases to selectively cleave new targets of therapeutic significance (click to read).
Sickle cell disease is an autosomal recessive genetic disease caused by mutations in HBB, usually encoding adult β-globin (βA).
Under low oxygen concentrations, mutant β-globin (βS) causes hemoglobin in red blood cells (RBC) to polymerize, resulting in characteristic sickle red blood cells and a series of hemolysis, inflammation, and capillary occlusion.
Symptoms include anemia, severe acute and chronic pain, immune deficiency, multiple organ failure, and premature death.
Although allogeneic hematopoietic stem cell (HSC) transplantation can cure SCD, it is usually not possible to obtain the best matched donor, and the procedure may result in transplant rejection or graft-versus-host disease.
The in vitro modification of autologous HSCs to avoid the harmful effects of SCD mutations is the basis of several experimental therapies.
Methods that have shown early clinical prospects include ectopic expression of anti-sickle β-like globin genes through lentiviral vectors and induction of fetal hemoglobin (HbF) through inhibition or Cas9-mediated destruction of BCL11A.
However, lentiviral vectors have the risk of inserting mutations and may not be able to effectively inhibit the expression of pathological βS.
Gene manipulation that induces HbF expression does not eliminate βS, and when mediated by double-stranded DNA breaks (DSB), it can cause indels, translocations, loss of large chromosomal fragments, chromosomal fragmentation, and p53 activation.
Cas9 nuclease-mediated homology-directed repair can correct HBBS, but it is difficult to repopulate HSC effectively and DSB is also required.
Elimination of SCD by converting HBBS alleles into benign variants without introducing DSB can overcome these limitations.
The adenine base editor (ABE) converts target A•T base pairs in living cells to G•C, without the need for DSB or donor DNA templates, and minimal indel formation.
In SCD, the GAG (Glu) codon encoding the 6th amino acid position of β-globin is mutated to GTG (Val).
Although adenine base editing cannot restore this mutation, it can convert the pathogenic codon into GCG (Ala), resulting in a naturally occurring non-pathogenic variant called Hb-Makassar (HBBG).
The graduate student became an ABE (ABE8e-NRCH), which converted the SCD allele into the non-pathogenic HBBG Makassar allele, and performed minimal non-silent bystander editing in the CD34+ HSPC of SCD patients.
The edited HSPC is persistent after implantation in mice, the frequency of HBBG at 16 weeks after transplantation is 68%, and the sickle cells in the derived red blood cells are significantly reduced.
To assess the phenotype, the study edited HSPC from a mouse model of SCD, in which the endogenous β-globin gene was replaced by human HBBS, and transplanted the edited HSPC into irradiated adult recipient mice.
The first and second transplantation of the edited mouse HSPC confirmed the editing in the long-term HSC and restored the hematological parameters to near normal levels.
These findings indicate that autologous ex vivo base editing and transplantation of HSC is a potential one-time treatment for SCD.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, and interested parties.
Long press or scan the QR code below to follow us.
iNature sickle cell disease is an autosomal recessive genetic disease caused by mutations in HBB, usually encoding adult β-globin (βA).
Although allogeneic hematopoietic stem cell (HSC) transplantation can cure SCD, it is usually not possible to obtain the best matched donor, and the procedure may result in transplant rejection or graft-versus-host disease.
On June 2, 2021, David R.
Liu (Liu Ruqian) of the Broad Institute and other teams published a research paper titled "Base editing of haematopoietic stem cells rescues sickle cell disease in mice" in Nature online, which used a customized gland The purine base editor (ABE8e-NRCH) converts the SCD allele (HBBS) to Makassar β-globin (HBBG), which is a non-pathogenic variant.
The delivery of mRNA encoding the base editor and targeting guide RNA in vitro to the hematopoietic stem and progenitor cells (HSPC) of SCD patients resulted in the conversion of 80% of HBBS to HBBG.
After 16 weeks of transplanting edited human HSPC into immunodeficient mice, the frequency of HBBG was 68%, and hypoxia-induced bone marrow reticulocyte sickle cells decreased by 5 times, indicating that gene editing is durable.
In order to evaluate the physiological effects of HBBS base editing, the study provided ABE8e-NRCH and introduced RNA from humanized SCD mice into HSPC, and then transplanted these cells into irradiated mice.
Sixteen weeks later, Makassar β-globin accounted for 79% of the β-globin in the blood, and sickle cells caused by hypoxia were reduced by three times.
Compared with mice that received unedited cells, mice that received base-edited HSPC showed near-normal hematological parameters and reduced splenic pathology.
The second transplantation of edited bone marrow confirmed that gene editing is durable in long-term hematopoietic stem cells and showed that 20% or more HBBS-to-HBBG editing is sufficient for phenotypic rescue.
The base editing of human HSPC avoids the p53 activation and larger deletions observed after Cas9 nuclease treatment.
In summary, these findings indicate that a one-time autotherapy of SCD can eliminate pathogenic HBBS, produce benign HBBG, and minimize the adverse consequences of double-stranded DNA breaks.
In addition, on February 19, 2021, David R.
Liu from the Broad Institute and Dong Min from Harvard Medical School jointly published a research paper entitled "Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity" in Science Online.
This research developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light chain proteases.
The research evolved BoNT/X protease into separate variants, which preferentially cleave vesicle-associated membrane protein 4 (VAMP4) and Ykt6, and evolved BoNT/F protease to selectively cleave the unnatural substrate VAMP7, and evolved BoNT/E protease cleaves phosphatase and tendon homologous protein (PTEN), but is not any natural BoNT protease substrate in neurons.
The evolved proteases show large changes in specificity (218-fold to 11,000,000-fold) and can retain their ability to form holotoxins that are self-delivered to primary neurons.
These findings establish a universal platform for reprogramming proteases to selectively cleave new targets of therapeutic significance (click to read).
Sickle cell disease is an autosomal recessive genetic disease caused by mutations in HBB, usually encoding adult β-globin (βA).
Under low oxygen concentrations, mutant β-globin (βS) causes hemoglobin in red blood cells (RBC) to polymerize, resulting in characteristic sickle red blood cells and a series of hemolysis, inflammation, and capillary occlusion.
Symptoms include anemia, severe acute and chronic pain, immune deficiency, multiple organ failure, and premature death.
Although allogeneic hematopoietic stem cell (HSC) transplantation can cure SCD, it is usually not possible to obtain the best matched donor, and the procedure may result in transplant rejection or graft-versus-host disease.
The in vitro modification of autologous HSCs to avoid the harmful effects of SCD mutations is the basis of several experimental therapies.
Methods that have shown early clinical prospects include ectopic expression of anti-sickle β-like globin genes through lentiviral vectors and induction of fetal hemoglobin (HbF) through inhibition or Cas9-mediated destruction of BCL11A.
However, lentiviral vectors have the risk of inserting mutations and may not be able to effectively inhibit the expression of pathological βS.
Gene manipulation that induces HbF expression does not eliminate βS, and when mediated by double-stranded DNA breaks (DSB), it can cause indels, translocations, loss of large chromosomal fragments, chromosomal fragmentation, and p53 activation.
Cas9 nuclease-mediated homology-directed repair can correct HBBS, but it is difficult to repopulate HSC effectively and DSB is also required.
Elimination of SCD by converting HBBS alleles into benign variants without introducing DSB can overcome these limitations.
The adenine base editor (ABE) converts target A•T base pairs in living cells to G•C, without the need for DSB or donor DNA templates, and minimal indel formation.
In SCD, the GAG (Glu) codon encoding the 6th amino acid position of β-globin is mutated to GTG (Val).
Although adenine base editing cannot restore this mutation, it can convert the pathogenic codon into GCG (Ala), resulting in a naturally occurring non-pathogenic variant called Hb-Makassar (HBBG).
The graduate student became an ABE (ABE8e-NRCH), which converted the SCD allele into the non-pathogenic HBBG Makassar allele, and performed minimal non-silent bystander editing in the CD34+ HSPC of SCD patients.
The edited HSPC is persistent after implantation in mice, the frequency of HBBG at 16 weeks after transplantation is 68%, and the sickle cells in the derived red blood cells are significantly reduced.
To assess the phenotype, the study edited HSPC from a mouse model of SCD, in which the endogenous β-globin gene was replaced by human HBBS, and transplanted the edited HSPC into irradiated adult recipient mice.
The first and second transplantation of the edited mouse HSPC confirmed the editing in the long-term HSC and restored the hematological parameters to near normal levels.
These findings indicate that autologous ex vivo base editing and transplantation of HSC is a potential one-time treatment for SCD.
Reference message: https://
