Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease
Abstract
:1. Introduction
2. HSC-Targeted Gene Therapy with Lentiviral Gene Addition in SCD
2.1. HSC Collection from Patients with SCD
2.2. HSC Culture Conditions for Gene Addition and Engraftment
2.3. Myeloablative Conditioning for Engraftment of Gene-Modified Cells
2.4. Potential Insertional Mutagenesis in Gene-Addition Therapy
2.5. Clinical Trials of Gene-Addition Therapy in SCD and β-Thalassemia
3. HSC-Targeted Gene-Editing Therapy in SCD
3.1. Endogenous DNA Repair Mechanisms
3.2. Engineered Endonucleases for Site-Specific DNA Break
3.3. Gene-Editing Delivery Methods
3.4. Gene Correction of the SCD Mutation with Gene Editing
3.5. Fetal Hemoglobin (HbF) Induction with Gene Editing
3.6. Base-Editing in SCD
3.7. Off-Target Effects with Gene Editing
3.8. Clinical Trials of Gene-Editing Therapy in SCD and β-Thalassemia
4. In Vivo Gene Editing for SCD
4.1. In Vivo Delivery with AAV Vectors
4.2. In Vivo Delivery with Ad Vectors
4.3. In Vivo Delivery with LVs
4.4. In vivo Delivery with Virus-Like Particles (VLPs)
4.5. In Vivo Delivery with LNPs
4.6. In Vivo Delivery with Polymer Nanoparticles (PNPs)
4.7. In Vivo Delivery with AuNPs
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Trial | Phase | Year | Study Drug | Target Gene | HSC Source | Conditioning | Sponsor | Location | Reference |
---|---|---|---|---|---|---|---|---|---|
Sickle cell disease | |||||||||
NCT04628585 | N/A | 2020 | BB305 | βT87Q-globin | N/A | N/A | bluebird bio | USA, France | [62] |
NCT04293185 | 3 | 2020 | BB305 | βT87Q-globin | Plerixafor mobilization | Myeloablative busulfan | bluebird bio | USA | N/A |
NCT04091737 | 1 | 2019 | CSL200 | γG16D-globin, shRNA-HPRT | Plerixafor mobilization | RIC melphalan | CSL Behring | USA | N/A |
NCT03964792 | 1/2 | 2019 | GLOBE1 | βAS3-globin | Plerixafor mobilization | Myeloablative busulfan | APHP | France | [68,69] |
NCT03282656 | 1 | 2018 | BCH-BB694 | shmiR-BCL11A | BM | Myeloablative busulfan | Boston Children’s Hospital | USA | [74] |
NCT02247843 | 1/2 | 2014 | βAS3-FB | βAS3-globin | Plerixafor mobilization | Myeloablative busulfan | University of California, Los Angeles | USA | N/A |
NCT02186418 | 1/2 | 2014 | ARU-1801 | γ-globin | BM/Plerixafor mobilization | RIC melphalan | Aruvant Sciences | USA, Canada, Jamaica | [72] |
NCT02140554 | 1/2 | 2014 | BB305 | βT87Q-globin | BM (Group A/B), Plerixafor mobilization (Group C) | Myeloablative busulfan | bluebird bio | USA | [38] |
NCT02151526 | 1/2 | 2013 | BB305 | βT87Q-globin | BM | Myeloablative busulfan | bluebird bio | France | [62,68] |
β-Thalassemia | |||||||||
NCT05015920 | 1 | 2021 | BD211 | βT87Q-globin | BM | Myeloablative busulfan | Shanghai Bdgene | China | N/A |
NCT04592458 | 1 | 2020 | LentiHBBT87Q | β-globin | BM | N/A | Shenzhen Children’s Hospital, BGI-Research | China | N/A |
NCT03207009 | 3 | 2017 | BB305 | βT87Q-globin | G-CSF and plerixafor mobilization | Myeloablative busulfan | bluebird bio | USA, France, Germany, Greece, Italy, UK | [65] |
NCT02906202 | 3 | 2016 | BB305 | βT87Q-globin | G-CSF and plerixafor mobilization | Myeloablative busulfan | bluebird bio | USA, France, Germany, Italy, Thailand, UK | [65] |
NCT02453477 | 1/2 | 2015 | GLOBE | β-globin | G-CSF and plerixafor mobilization | Myeloablative treosulfan/thiotepa | TIGET | Italy | [68] |
NCT01745120 | 1/2 | 2013 | BB305 | βT87Q-globin | BM | Myeloablative busulfan | bluebird bio | USA, Australia, Thailand | [64] |
NCT02151526 | 1/2 | 2013 | BB305 | βT87Q-globin | BM | Myeloablative busulfan | bluebird bio | France | [64] |
NCT02633943 | N/A | 2013 | BB305 | BM/G-CSF and plerixafor mobilization | Myeloablative busulfan | bluebird bio | USA, Australia, France, Germany, Italy, Thailand, UK | [62] | |
NCT01639690 | 1 | 2012 | TNS9.3.55 | β-globin | G-CSF mobilization | RIC busulfan | Memorial Sloan Kettering | USA | [45,67] |
LG001 | 1/2 | 2007 | BM | Myeloablative busulfan | bluebird bio | France | [50,60] |
Trial | Phase | Year | Study Drug | Target Gene | HSC Source | Conditioning | Sponsor | Location | Reference |
---|---|---|---|---|---|---|---|---|---|
Sickle cell disease | |||||||||
NCT04774536 | 1/2 | 2021 | CRISPR/Cas9: CRISPR_SCD001 | β-globin | BM | Myeloablative Busulfan | University of California, San Francisco | USA | N/A |
NCT04853576 | 1/2 | 2021 | CRISPR/Cas12: EDIT-301 | BCL11A ESE | Plerixafor mobilization | Myeloablative busulfan | Editas Medicine | USA | N/A |
NCT04819841 | 1/2 | 2021 | CRISPR/Cas9: GPH101 | β-globin | BM | Myeloablative busulfan | Graphite Bio | USA | N/A |
NCT05145062 | N/A | 2021 | ZFN: BIVV003 | BCL11A ESE | Plerixafor mobilization | Myeloablative busulfan | Bioverativ | USA | [142] |
NCT04443907 | 1/2 | 2020 | CRISPR/Cas9: OTQ923 / HIX763 | BCL11A ESE | N/A | N/A | Novartis Pharmaceuticals | USA | N/A |
NCT03653247 | 1/2 | 2019 | ZFN: BIVV003 | BCL11A ESE | Plerixafor mobilization | Myeloablative busulfan | Bioverativ | USA | [142] |
NCT04208529 | N/A | 2019 | CRISPR/Cas9: CTX001 | BCL11A ESE | BM | Myeloablative busulfan | Vertex Pharmaceuticals | USA | [144] |
NCT03745287 | 2/3 | 2018 | CRISPR/Cas9: CTX001 | BCL11A ESE | BM | Myeloablative busulfan | Vertex Pharmaceuticals | USA | [144] |
β-Thalassemia | |||||||||
NCT04205435 | 1/2 | 2021 | CRISPR/Cas9 | β-globin | N/A | N/A | Biorary Laboratories | China | N/A |
NCT04208529 | N/A | 2021 | CRISPR/Cas9: CTX001 | BCL11A ESE | BM | Myeloablative busulfan | Vertex Pharmaceuticals | USA | [144] |
NCT04211480 | 1/2 | 2020 | CRISPR/Cas9 | BCL11A ESE | N/A | N/A | Biorary Laboratories | China | N/A |
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Germino-Watnick, P.; Hinds, M.; Le, A.; Chu, R.; Liu, X.; Uchida, N. Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease. Cells 2022, 11, 1843. https://doi.org/10.3390/cells11111843
Germino-Watnick P, Hinds M, Le A, Chu R, Liu X, Uchida N. Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease. Cells. 2022; 11(11):1843. https://doi.org/10.3390/cells11111843
Chicago/Turabian StyleGermino-Watnick, Paula, Malikiya Hinds, Anh Le, Rebecca Chu, Xiong Liu, and Naoya Uchida. 2022. "Hematopoietic Stem Cell Gene-Addition/Editing Therapy in Sickle Cell Disease" Cells 11, no. 11: 1843. https://doi.org/10.3390/cells11111843