β-Thalassemia is an autosomal recessive disease caused by mutations in the HBB gene that result in the production of insufficient HBB protein . Unlike sickle cell disease, the mutations that cause β-thalassemia are scattered throughout the HBB gene, including in the regulatory and pre-mRNA splicing elements. NHEJ and HDR approaches to β-thalassemia are being developed.

Fetal Hemoglobin Derepression

HbF upregulation, as described for sickle cell disease, is also an approach to treating β-thalassemia. By upregulating gamma-globin, the missing beta-globin is compensated for and unpaired alpha globin chain precipitates would be prevented. The genome editing approaches for β-thalassemia to upregulate HbF are identical to those being used for sickle cell disease. The early clinical results for inactivating the erythroid specific enhancer of BCL11A show great promise with patients becoming transfusion independent within months of treatment and stable total Hb levels greater than 12, with essentially all of the Hb being HbF.[1] The long-term safety and efficacy of having such high levels of HbF are being evaluated, although patients with HPFH suggest that it is a relatively healthy condition.

Knocking HBB into HBA1

An HR approach to β-thalassemia has been described in which the HBB gene was knocked-into the HBA1 gene without disrupting the HBA2 gene (called “whole gene replacement”).[2] In this way, more HBB protein and less HBA protein is made, thus correcting the chain imbalance that is a key pathology in the disease. This can be considered a form of synthetic biology because the genome is being engineered such that one gene (HBB) is now being expressed instead of another gene (HBA1) through the HBA1 natural regulatory elements. In preclinical work, the ratio of beta-globin protein to alpha-globin protein was increased to the β-thalassemia trait level of 0.5 when red blood cells were evaluated from genome-edited HSPCs derived from β-thalassemia major patients. This expression level should mimic β-thalassemia trait.

References

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[1] Frangoul H, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. N Engl J Med. 2021;384(3):252–260.

[2] Cromer MK, et al. Gene replacement of alpha-globin with beta-globin restores hemoglobin balance in beta-thalassemia-derived hematopoietic stem and progenitor cells. Nat Med. 2021;27(4):677–687.

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مواضيع ذات صلة

Genome Editing of Immune Effector Cells for Safer and More Potent Cancer Therapies (CAR-T Cells)

Therapeutic Genome Editing for Hematologic Diseases: Sickle Cell Disease

TFIIIA Binding to the Middle of its Gene as Well as to RNA

Biology of 5S RNA Synthesis in Xenopus

Entropy, a Basis for Lambda Repressor Inactivation

Induction from the Lysogenic State

The Need for and the Realization of Hair-Trigger Induction

Site for Cro Repression and CI Activation

Chronology of Becoming a Lysogen

N Protein and Antitermination of Early Gene Transcription

Spontaneous Mutations in bacteria

Mechanisms of Gene Transfer in Bacteria