Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy
Abstract
:1. Introduction
2. Clinical Presentation of DBA and Diagnosis
3. Molecular Mechanism of DBA
4. Existing Treatment Options for DBA
5. Gene Therapy for DBA—From Research Now to Clinic in the Future
5.1. Lentiviral Vectors as a Potential Gene Therapy Approach for DBA
5.2. CRISPR/Cas9 Non-Integrating Lentiviral-Based Gene Therapy
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Disease | Clinical Trial ID | Intervention/Treatment | Ref. |
---|---|---|---|
Sickle Cell Disease (SCD) | NCT02186418 | CD34+ cells transduced with gamma-globin lentiviral vector. | [32] |
NCT03282656 | Single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a. | [33] | |
NCT05353647 | Autologous transplantation of CD34+ HSC cells transduced with the lentiviral vector containing a shRNA targeting BCL11a. | [34] | |
NCT02247843 | Autologous transplantation of peripheral blood CD34+ cells transduced ex vivo by the Lenti/G-βAS3-FB lentiviral vector to express an anti-sickling (βAS3) gene. | [35] | |
NCT03964792 | Transplantation of an autologous CD34+ enriched cell fraction that contains CD34+ cells transduced ex vivo with the GLOBE1 lentiviral vector expressing the βAS3 globin gene (GLOBE1 βAS3 modified autologous CD34+ cells). | [36] | |
SCD and β-Thalassemia | NCT02151526 | Administration of LentiGlobin BB305 drug product to participants with either transfusion dependent β-thalassemia (TDT) or sickle cell disease (SCD). | [37] |
β-Thalassemia | NCT03276455 | Autologous transplantation of HSCs transduced with lentiviral vector encoding for beta-globin gene. | [38] |
NCT02453477 | Autologous transplantation of HSCs genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene. | [39] | |
NCT06219239 | Autologous transplantation of HSCs transduced with lentiviral vector encoding βA-T87Q-globin gene. | [40] | |
NCT05745532 | Autologous transplantation of HSCs transduced with LentiHBBT87Q system to restore β-globin expression. | [41] | |
NCT06280378 | Autologous transplantation of CD34+ stem cells transduced ex vivo with a lentiviral vector encoding βA-T87Q-globin. | [42] | |
NCT01639690 | Autologous transplantation of CD34+ cells transduced with TNS9.3.55 lentiviral vector encoding the normal human ß-globin gene. | [43] | |
NCT05762510 | Autologous transplantation of CD34+ HSCs transduced with LentiRed lentiviral vector. | [44] | |
NCT05757245 | Autologous HSCT using GMCN-508A drug product (autologous CD34+ HSCs transduced with GMCN-508A lentiviral vector encoding the human α-globin gene). | [45] | |
NCT05015920 | Transplantation of autologous CD34+ stem cells transduced with a lentiviral vector encoding βA-T87Q-globin. | [46] | |
Fanconi Anemia (FA) | NCT01331018 | Transplantation of autologous patient blood stem cells that have been corrected in the laboratory by introduction of the normal FANCA gene. | [47] |
NCT04437771 | Transplantation of autologous CD34+ cells transduced with lentiviral vector carrying the FANCA gene. | [48] |
Aspect | Integrating Lentiviral Vectors (ILVs) | Non-Integrating Lentiviral Vectors (NILVs) |
---|---|---|
Integration | Integrates the transgene into the host genome [22,50] | Does not integrate the transgene into the host genome [52] Expresses the transgene from episomal DNA in non-dividing cells or transiently in dividing cells [49] |
Expression | Stable integration of the transgene into the host genome [49,50] | Enables transient expression or sustained episomal expression [50] |
Safety | Higher risk of insertional mutagenesis and malignant transformation [50] | Reduced risk of insertional mutagenesis and malignant transformation [50] |
Applications | Gene therapy for long-term gene expression [50,52] Recombinant protein production [50] Vaccination [50] Cell imaging [50] | Gene therapy for mutation correction [50,52] Cytotoxic cancer therapies [49,50] Cellular differentiation [49] Vaccination [49,52] Immunotherapies [49,50] |
Limitations | Insertional mutagenesis [24] Oncogenic potential [24] | Residual integration risks [50] Transient expression is not suitable for all applications |
Tools | Components | Applicability | Advantages | Drawbacks | Ref. |
---|---|---|---|---|---|
CRISPR/Cas9 | Cas9, sgRNA, and donor DNA (for HDR) | Point mutations Large DNA insertions and deletions Gene knock-out | Versatility in gene insertion, deletion, and modification | DSB induction Off-target effects Low efficiency for HDR | [56] |
CBE | dCa9-cytosine deaminase, and sgRNA | Transitions mutations (C→T, G→A, A→G, T→C) | Induction of SSBs | Requires precise positioning of editing window Off-target DNA and RNA editing Bystander edits Only capable of four transition mutations | [56,57] |
ABE | dCas9-adenine deaminase and sgRNA | ||||
PE | dCas9(H840A)-M-MLV RT and pegRNA | Point mutations Small deletions and insertions | Induction of SSBs Allows for all precise modifications | Genomic scope constraints Variable efficiency in different cell types Delivery challenges due to large size of PE | [56,58] |
Disease | Clinical Trial ID | Intervention/Treatment | Ref |
---|---|---|---|
Sickle Cell Disease (SCD) | NCT06287099 | Autologous CRISPR/Cas9 modified CD34+ hHSPCs (BRL-101) | [64] |
NCT04819841 | Gene correction in autologous CD34+ HSCs (HbS to HbA) to treat severe SCD | [65] | |
NCT03745287 | Autologous CRISPR/Cas9 modified CD34+ hHSPCs using CTX001 | [66] | |
NCT05951205 | Single dose of CTX001 in subjects with severe SCD with βS/βC genotype | [67] | |
NCT04774536 | Transplantation of CRISPR/Cas9 corrected HSCs (CRISPR_SCD001) in patients with severe SCD | [68] | |
NCT05329649 | Administration of a single dose of CTX001 in pediatric subjects with severe SCD | [69] | |
SCD and β-Thalassemia | NCT05477563 | Single dose of autologous CRISPR/Cas9 modified CD34+ hHSPCs (CTX001) in subjects with transfusion-dependent β-Thalassemia or severe SCD | [70] |
NCT04208529 | A long-term follow-up study of subjects with β-thalassemia or SCD treated with autologous CRISPR/Cas9 modified HSCs (CTX001) | [71] | |
β-Thalassemia | NCT03655678 | Autologous CRISPR/Cas9 modified CD34+ hHSPCs using CTX001 in subjects with transfusion-dependent β-Thalassemia | [72] |
NCT04925206 | Autologous CRISPR/Cas9 modified CD34+ hHSPCs using ET-01 in subjects with transfusion-dependent β-Thalassemia | [73] | |
NCT05577312 | Autologous CRISPR/Cas9 modified CD34+ hHSPCs (BRL-101) | [74] | |
NCT05356195 | Autologous CRISPR/Cas9 modified CD34+ hHSPCs (CTX001) in pediatric subjects with transfusion-dependent β-Thalassemia | [75] | |
NCT03728322 | Gene correction of HBB in patient-specific iHSCs using CRISPR/Cas9 | [76] |
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Vale, M.; Prochazka, J.; Sedlacek, R. Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy. Cells 2024, 13, 920. https://doi.org/10.3390/cells13110920
Vale M, Prochazka J, Sedlacek R. Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy. Cells. 2024; 13(11):920. https://doi.org/10.3390/cells13110920
Chicago/Turabian StyleVale, Matilde, Jan Prochazka, and Radislav Sedlacek. 2024. "Towards a Cure for Diamond–Blackfan Anemia: Views on Gene Therapy" Cells 13, no. 11: 920. https://doi.org/10.3390/cells13110920