Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease
Open accessAbstract
BACKGROUND: is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. METHODS: mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment. RESULTS: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. CONCLUSIONS: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).
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Erythroid-specific BCL11A knockdown via lentiviral shRNA reactivates γ-globin and is in early clinical development.
“an erythroid-specific knockdown of BCL11A delivered by a lentiviral-encoded, microRNA-adapted short hairpin RNA molecule has been shown to reactivate the γ-globin gene and is in early clinical development.[17][18][19]”
From CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia (2021) · cites this paper as [19]
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- Authors
- Esrick, E. B., Lehmann, L. E., Biffi, A., Achebe, M., Brendel, C., Ciuculescu, M. F., Daley, H., MacKinnon, B., Morris, E., Federico, A., Abriss, D., Boardman, K., Khelladi, R., Shaw, K., Negre, H., Negre, O., Nikiforow, S., Ritz, J., Pai, S.-Y., London, W. B., Dansereau, C., Heeney, M. M., Armant, M., Manis, J. P., & Williams, D. A.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- From the Dana–Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School (E.B.E., L.E.L., A.B., C.B., M.F.C., B.M., K.B., S.-Y.P., W.B.L., C.D., M.M.H., D.A.W.), the Harvard Stem Cell Institute, Harvard Medical School (A.B., C.B.), the Gene Therapy Program, Dana–Farber/Boston Children’s Cancer and Blood Disorders Center (A.B., M.F.C., B.M., E.M., A.F., S.-Y.P., C.D., D.A.W.), the Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School (M. Achebe), the...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-01-21
- Volume
- 384
- Issue
- 3
- Pages
- 205-215
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC7962145
- OpenAlex
- W3111094104
- Cited by
- 449
- References
- 44
- Citations by year
- 2026: 50 · 2025: 63 · 2024: 87 · 2023: 83 · 2022: 82 · 2021: 80 · 2020: 3 · 2019: 1
- FWCI
- 32.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Funders
- National Heart, Lung, and Blood Institute (5R01HL137848)
- Celine Dion
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Keywords
- sickle cell disease, BCL11A, fetal hemoglobin induction, shRNA, post-transcriptional gene silencing, gene therapy, engraftment
- MeSH terms
- Adolescent, Adult, Anemia, Sickle Cell, Child, Female, Fetal Hemoglobin, Genetic Vectors, Humans, Male, Pilot Projects, Repressor Proteins, Transplantation, Autologous, Genetic Therapy, Down-Regulation, RNA Interference, RNA, Small Interfering, gamma-Globins, Gene Knockdown Techniques, Young Adult
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