Gene therapy: Erasing sickle-cell disease

Autologous transplantation of gene-modified HSCs might be used to treat Sickle Cell Disease (SCD) once and for all. Hematopoietic Stem Cell (HSC) gene therapy with lentiviral-globin gene addition was optimized by HSC collection, vector constructs, lentiviral transduction, and conditioning in the current gene therapy experiment for SCD, resulting in higher gene marking and phenotypic correction. Further advancements over the next decade should allow for a widely approved gene-addition therapy. Long-term engraftment is crucial for gene-corrected CD34+ HSCs, which might be addressed in the coming years, and gene repair of the SCD mutation in the-globin gene can be achieved in vitro using genome editing in CD34+ cells. Because of breakthroughs in efficacy, safety, and delivery strategies, in vivo gene addition and gene correction in BM HSCs is advancing. Overall, further research is needed, but HSC-targeted gene addition/gene editing therapy is a promising SCD therapy with curative potential that might be widely available soon.

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Gene therapy for sickle cell disease

10.1002/14651858.cd007652.pub4 ◽

2014 ◽

Cited By ~ 4

Author(s):

Abiola Olowoyeye ◽

Charles I Okwundu

Keyword(s):

Gene Therapy ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Cell Disease

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Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both or neither

Blood ◽

10.1182/blood.2021011488 ◽

2021 ◽

Author(s):

Rick J. Jones ◽

Michael R DeBaun

Keyword(s):

Gene Therapy ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Insertional Mutagenesis ◽

Absolute Risk ◽

Cell Disease ◽

Post Transplantation ◽

Curative Therapy ◽

Gene Therapy Trial ◽

Safe Strategy

Recently, encouraging data provided long-awaited hope for gene therapy as a cure for sickle cell disease (SCD). Nevertheless, the suspension of the bluebird bio gene therapy trial (ClinicalTrials.gov: NCT02140554) after participants developed acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) is concerning. Potential possibilities for these cases include busulfan, insertional mutagenesis, both or neither. Busulfan was considered the cause in the first reported case, as the transgene was not present in the AML/MDS. However, busulfan is unlikely to have contributed to the most recent case. The transgene was present in the patient's malignant cells, indicating they were infused after busulfan treatment. Several lines of evidence suggest an alternative explanation for events in the bluebird bio trial, including that SCD population studies show an increased relative, but a low absolute, risk of AML/MDS. We propose a new hypothesis: after gene therapy for SCD, the stress of switching from homeostatic to regenerative hematopoiesis by transplanted cells drives clonal expansion and leukemogenic transformation of pre-existing premalignant clones, eventually resulting in AML/MDS. Evidence validating our hypothesis will support pre-screening individuals with SCD for pre-leukemic progenitors before gene therapy. Until a viable, safe strategy has been implemented to resume gene therapy in adults with severe SCD, reasonable alternative curative therapy should be considered for children and adults with severe SCD. Currently, open multi-center clinical trials are incorporating nonmyeloablative conditioning, related haploidentical donors, and post-transplantation cyclophosphamide. Preliminary results from these trials appear promising and NIH-sponsored trials are ongoing in pediatric and adult individuals with SCD using this platform.

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Primary caregiver decision‐making in hematopoietic cell transplantation and gene therapy for sickle cell disease

Pediatric Blood & Cancer ◽

10.1002/pbc.28749 ◽

2020 ◽

Vol 68 (1) ◽

Author(s):

Cynthia B. Sinha ◽

Nitya Bakshi ◽

Diana Ross ◽

George Loewenstein ◽

Lakshmanan Krishnamurti

Keyword(s):

Decision Making ◽

Gene Therapy ◽

Sickle Cell Disease ◽

Cell Transplantation ◽

Sickle Cell ◽

Hematopoietic Cell Transplantation ◽

Primary Caregiver ◽

Hematopoietic Cell ◽

Cell Disease

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Pre-clinical Development of a Lentiviral Vector Expressing the Anti-sickling βAS3 Globin for Gene Therapy for Sickle Cell Disease

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2018.10.014 ◽

2018 ◽

Vol 11 ◽

pp. 167-179 ◽

Cited By ~ 5

Author(s):

Valentina Poletti ◽

Fabrizia Urbinati ◽

Sabine Charrier ◽

Guillaume Corre ◽

Roger P. Hollis ◽

...

Keyword(s):

Gene Therapy ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Lentiviral Vector ◽

Clinical Development ◽

Cell Disease

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