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Medical Science Monitor : International... Mar 2024In 2020, Emmanuelle Charpentier and Jennifer Doudna were awarded the Nobel Prize in Chemistry for their research on the endonuclease, clustered regularly interspaced...
In 2020, Emmanuelle Charpentier and Jennifer Doudna were awarded the Nobel Prize in Chemistry for their research on the endonuclease, clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated protein 9 (CRISPR-Cas9) method for DNA editing. On 16 November 2023, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) was the first to approve the CRISPR-Cas9 gene editing therapy, Casgevy (exagamglogene autotemcel), for the treatment of patients with transfusion-dependent b-thalassemia and the treatment of sickle cell disease in patients aged ≥12 years with recurrent vaso-occlusive crises. On 8 December 2023, the US Food and Drug Administration (FDA) approved both Casgevy and Lyfgenia (lovotibeglogene autotemcel) for patients with sickle cell disease. On 15 December 2023, the European Medicines Agency (EMA) approved Casgevy for sickle cell disease and transfusion-dependent ß-thalassemia. This Editorial aims to present an update on the landmark first regulatory approvals of CRISPR-Cas9 for patients with sickle cell disease and transfusion-dependent b-thalassemia and the potential challenges for therapeutic gene (DNA) editing.
Topics: United States; Humans; Gene Editing; CRISPR-Cas Systems; beta-Thalassemia; Anemia, Sickle Cell; DNA
PubMed: 38425279
DOI: 10.12659/MSM.944204 -
La Revue de Medecine Interne Nov 2023Sickle cell disease is syndromic, associating a hemolytic anemia, a vaso-obstructive vascular disease, and an infectious risk linked to the precocity of the splenic...
Sickle cell disease is syndromic, associating a hemolytic anemia, a vaso-obstructive vascular disease, and an infectious risk linked to the precocity of the splenic function loss. The willingly hyperacute and potentially fatal character of the two last elements of the pathophysiologic syndrome, has, quite rightly, focused the therapeutic researches on them. Great success in those two domains have allowed a very important gain in life expectancy. However, chronic progressive organ dysfunction began to appear in older than 25 years-old patients. It concerns mainly renal, hepatic, cardiac functions and pulmonary arterial pressure and may lead to organ failure and premature death. Since some 25 years, the clinical research demonstrated an association between such complications and intravascular hemolytic rate, and it turned to a causative relationship. This present paper try to summarize the actual knowledge on the structural and genetic aspects of sickle cell anemia hemolysis. © 2023 Société nationale française de médecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.
Topics: Humans; Aged; Adult; Anemia, Sickle Cell; Hemolysis; Erythrocytes; Vascular Diseases; Syndrome
PubMed: 38049243
DOI: 10.1016/S0248-8663(23)01302-4 -
Human Gene Therapy Sep 2023β-Thalassemia and sickle cell disease are autosomal recessive disorders of red blood cells due to mutations in the adult β-globin gene, with a worldwide diffusion. The... (Review)
Review
β-Thalassemia and sickle cell disease are autosomal recessive disorders of red blood cells due to mutations in the adult β-globin gene, with a worldwide diffusion. The severe forms of hemoglobinopathies are fatal if untreated, and allogeneic bone marrow transplantation can be offered to a limited proportion of patients. The unmet clinical need and the disease incidence have promoted the development of new genetic therapies based on the engineering of autologous hematopoietic stem cells. Here, the steps of gene therapy development are reviewed along with results from clinical trials and recent new approaches employing cutting edge gene editing tools.
Topics: Adult; Humans; Hemoglobinopathies; Anemia, Sickle Cell; beta-Thalassemia; Genetic Therapy; Gene Editing
PubMed: 37675899
DOI: 10.1089/hum.2023.138 -
Blood Reviews Mar 2024α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying... (Review)
Review
α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and β globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.
Topics: Humans; beta-Thalassemia; alpha-Thalassemia; Erythropoiesis; Hematologic Diseases; Erythrocyte Transfusion; Iron Overload
PubMed: 38182489
DOI: 10.1016/j.blre.2023.101165 -
La Revue de Medecine Interne Nov 2023Worsening of anemia is very common in sickle cell disease. It is important to investigate specific complications related to sickle cell disease but also other causes of...
Worsening of anemia is very common in sickle cell disease. It is important to investigate specific complications related to sickle cell disease but also other causes of anemia in general. Transfusions or exchange transfusions are major therapeutic options and are frequently used for acute complications of sickle cell disease but also for primary and secondary prevention of some of the chronic complications. The transfusion strategy has been modified since the awareness of post-transfusion hemolysis by taking into account the transfusion risk score. A strong collaboration between the patient's expert center, the Blood center and the patient's hospitalization unit is required to make decisions. © 2023 Société nationale française de médecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.
Topics: Humans; Adult; Anemia, Sickle Cell; Hemolysis; Transfusion Reaction; Secondary Prevention
PubMed: 38049241
DOI: 10.1016/S0248-8663(23)01304-8 -
La Revue de Medecine Interne Nov 2023Sickle cell anemia is a genetic disorder that affects hemoglobin leading to the production of an abnormal hemoglobin, called HbS. HbS has the property to polymerize...
Sickle cell anemia is a genetic disorder that affects hemoglobin leading to the production of an abnormal hemoglobin, called HbS. HbS has the property to polymerize under deoxygenated conditions, causing a mechanical distortion of red blood cells; a phenomenon called sickling. These sickle red blood cells are more fragile and rigid, leading to chronic hemolytic anemia and painful vaso-occlusive crises, as well as chronic vascular complications that can affect many organs. The abnormal functional properties of these sickle red blood cells are responsible for a wide range of clinical expression of the disease. HbS polymerization can be influenced by many factors, such as the hydration state of the red blood cells or the affinity of hemoglobin for oxygen. Moreover, the rheological characteristics of red blood cells, including their deformability and aggregation properties, are associated with specific clinical phenotypes. The pro-inflammatory and pro-oxidant state, as well as the repeated polymerization of HbS, accelerate the senescence of sickle red blood cells, promoting the release of microparticles and contributing to vascular dysfunction. Patients' red blood cells also have molecular characteristics that promote their adhesion to the endothelium and other circulating cells, contributing to the onset of vascular complications. Massive intravascular hemolysis, due to increased erythrocyte fragility, is also responsible for chronic vascular complications. These different alterations are privileged therapeutic targets, leading to the emergence of new specific treatments. © 2023 Société nationale française de médecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.
Topics: Humans; Anemia, Sickle Cell; Hemolysis; Erythrocytes, Abnormal; Oxygen; Hemoglobins
PubMed: 38049242
DOI: 10.1016/S0248-8663(23)01305-X -
Minerva Medica Dec 2023β-thalassemia is a monogenic disorder characterized by decreased hemoglobin production, resulting in chronic anemia. There are several factors affecting the clinical... (Review)
Review
β-thalassemia is a monogenic disorder characterized by decreased hemoglobin production, resulting in chronic anemia. There are several factors affecting the clinical presentation of patients with β-thalassemia, and several complications such as iron overload or ineffective erythropoiesis have been linked to this disease. Until nowadays, several conservative therapies namely blood transfusions, iron chelation, and the FDA-approved drug Luspatercept have been adopted alongside other debatable permanent cures. Other clinical trials are being conducted to develop better and safer management techniques for these patients. This review will discuss the different treatment strategies of β-thalassemia including novel therapies, besides all possible curative therapies that are being developed for this disease.
Topics: Humans; beta-Thalassemia; Iron Overload
PubMed: 37534831
DOI: 10.23736/S0026-4806.23.08501-4 -
La Revue de Medecine Interne Nov 2023Sickle Cell Anemia is a disease with a strong vascular tropism. Beyond anemia, the pathophysiological mechanisms responsible for hemolysis, directly affect both acute...
Sickle Cell Anemia is a disease with a strong vascular tropism. Beyond anemia, the pathophysiological mechanisms responsible for hemolysis, directly affect both acute and chronic vascular damages, thus resulting in a systemic disease. Understanding the different types of hemolysis underline the need for novel specific biomarkers. Targeted therapeutic approaches for these pathophysiological pathways are necessary to improve Sickle Cell patients' prognosis. Finally, given its complexity, Sickle Cell Disease is often used as a "proof of concept" for other pathologies. It seems likely that the rapidly evolving knowledge in this field will also benefit other diseases. © 2023 Société nationale française de médecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.
Topics: Humans; Hemolysis; Anemia, Sickle Cell; Biomarkers
PubMed: 38049244
DOI: 10.1016/S0248-8663(23)01303-6 -
CMAJ : Canadian Medical Association... Oct 2023
Topics: Humans; Erythrocyte Transfusion; Anemia, Sickle Cell
PubMed: 37816530
DOI: 10.1503/cmaj.221423-f -
Cell Stem Cell Dec 2023Reactivating silenced γ-globin expression through the disruption of repressive regulatory domains offers a therapeutic strategy for treating β-hemoglobinopathies....
Reactivating silenced γ-globin expression through the disruption of repressive regulatory domains offers a therapeutic strategy for treating β-hemoglobinopathies. Here, we used transformer base editor (tBE), a recently developed cytosine base editor with no detectable off-target mutations, to disrupt transcription-factor-binding motifs in hematopoietic stem cells. By performing functional screening of six motifs with tBE, we found that directly disrupting the BCL11A-binding motif in HBG1/2 promoters triggered the highest γ-globin expression. Via a side-by-side comparison with other clinical and preclinical strategies using Cas9 nuclease or conventional BEs (ABE8e and hA3A-BE3), we found that tBE-mediated disruption of the BCL11A-binding motif at the HBG1/2 promoters triggered the highest fetal hemoglobin in healthy and β-thalassemia patient hematopoietic stem/progenitor cells while exhibiting no detectable DNA or RNA off-target mutations. Durable therapeutic editing by tBE persisted in repopulating hematopoietic stem cells, demonstrating that tBE-mediated editing in HBG1/2 promoters is a safe and effective strategy for treating β-hemoglobinopathies.
Topics: Humans; Gene Editing; Fetal Hemoglobin; gamma-Globins; CRISPR-Cas Systems; Mutation; Hemoglobinopathies; Hematopoietic Stem Cells; Transcription Factors
PubMed: 37989316
DOI: 10.1016/j.stem.2023.10.007