Materials and methods for treatment of hemoglobinopathies
Inventors
Chakraborty, Tirtha • Mishra, Bibhu Prasad
Assignees
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Publication Number
US-12492388-B2
Publication Date
2025-12-09
Expiration Date
Abstract
Materials and methods for treating a patient with hemoglobinopathy, both ex vivo and in vivo and materials and methods for deleting at least a portion of a human beta globin locus on chromosome 11 in a human cell by genome editing and thereby increasing the production of fetal hemoglobin (HbF).
Core Innovation
The disclosure describes genome editing of the human beta globin locus on chromosome 11 using DNA endonucleases and sequence-defined single-molecule guide RNAs. The claimed editing creates a permanent deletion within or near the locus, including deletions spanning the delta- and beta-globin genes, and increases fetal hemoglobin in a human cell. The disclosed subject matter further encompasses specified guide RNA spacer alternatives, kits, genetically engineered cells carrying the deletion, and treatment approaches.
The provided subject matter identifies hemoglobinopathies as a treatment context, demonstrating that targeted chromosome 11 deletions elevate fetal hemoglobin and increase gamma-globin expression in differentiated erythroid cells. Cell viability, proliferation, differentiation, and enucleation remain generally similar between edited cells and controls. Successive editing is reported as potentially enhancing editing and fetal hemoglobin outcomes, though the background section is not explicitly described in patent.
Claims Coverage
The independent claims identify four inventive features directed to a method for editing the human beta globin locus, a single-molecule guide RNA, a guide RNA kit, and a genetically engineered cell.
Editing the human beta globin locus
The claim covers introducing DNA endonucleases and one or more single-molecule guide RNAs comprising specified spacer alternatives into a human cell to generate a permanent deletion within or near the human beta globin locus on chromosome 11 and increase fetal hemoglobin.
Sequence-defined single-molecule guide RNA
The claim covers a single-molecule guide RNA comprising a spacer sequence corresponding to one of the specified sequence alternatives.
Guide RNA kit
The claim covers a kit comprising at least one guide RNA selected from the specified spacer-sequence alternatives.
Genetically engineered cell with a permanent deletion
The claim covers a genetically engineered cell comprising a permanent deletion within or near the human beta globin locus at one or more sites targeted by sequence-defined guide RNAs.
The independent claims cover the locus-editing method, sequence-defined guide RNA compositions, a kit comprising the guide RNAs, and a genetically engineered cell carrying the resulting permanent deletion.
Stated Advantages
Editing selected human CD34+ cells with reported guide combinations increases gamma-globin expression and fetal hemoglobin in differentiated erythroid cells.
Edited cells exhibit viability, proliferation, erythroid differentiation, and enucleation generally similar to controls.
Successive editing is described as potentially improving editing and fetal hemoglobin outcomes.
Guide selection is described as favoring on-target editing while limiting off-target activity.
The described genomic editing is permanent and durable.
The described strategies reduce harmful beta-globin products.
Ex vivo approaches permit analysis of edited cells prior to patient implantation.
Documented Applications
Ex vivo treatment of hemoglobinopathies comprising editing a cell, differentiating the edited cell into a hematopoietic progenitor cell, and implanting the cell into a patient.
In vivo treatment of hemoglobinopathies by editing the human beta globin locus in a patient cell.
Treatment of sickle cell anemia or thalassemia using a population of genetically engineered cells.
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