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Successful gene the...
Successful gene therapy of Diamond-Blackfan anemia in a mouse model and human CD34+ cord blood hematopoietic stem cells using a clinically applicable lentiviral vector
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- Liu, Yang (author)
- Lund University,Lunds universitet,Hematopoes och genterapi,Forskargrupper vid Lunds universitet,Hematopoiesis and Gene Therapy,Lund University Research Groups
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- Dahl, Maria (author)
- Lund University,Lunds universitet,Hematopoes och genterapi,Forskargrupper vid Lunds universitet,Hematopoiesis and Gene Therapy,Lund University Research Groups
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- Debnath, Shubhranshu (author)
- Lund University,Lunds universitet,Hematopoes och genterapi,Forskargrupper vid Lunds universitet,Hematopoiesis and Gene Therapy,Lund University Research Groups
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- Rothe, Michael (author)
- Hannover Medical School
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- Smith, Emma (author)
- Lund University,Lunds universitet
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- Tan Grahn, Hooi Min (author)
- Lund University,Lunds universitet,Hematopoes och genterapi,Forskargrupper vid Lunds universitet,Hematopoiesis and Gene Therapy,Lund University Research Groups
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- Warsi, Sarah (author)
- Lund University,Lunds universitet,Hematopoes och genterapi,Forskargrupper vid Lunds universitet,Hematopoiesis and Gene Therapy,Lund University Research Groups
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- Chen, Jun (author)
- Lund University,Lunds universitet,Stamceller till röda blodkroppar,Forskargrupper vid Lunds universitet,Stem Cells to Red Blood Cells,Lund University Research Groups
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- Flygare, Johan (author)
- Lund University,Lunds universitet,Stamceller till röda blodkroppar,Forskargrupper vid Lunds universitet,Stem Cells to Red Blood Cells,Lund University Research Groups
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- Schambach, Axel (author)
- Hannover Medical School
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- Karlsson, Stefan (author)
- Lund University,Lunds universitet,Hematopoes och genterapi,Forskargrupper vid Lunds universitet,Hematopoiesis and Gene Therapy,Lund University Research Groups
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(creator_code:org_t)
- 2021-01-14
- 2022
- English.
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In: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 107:2, s. 446-456
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Abstract
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- Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure disorder in which pure red blood cell aplasia is associated with physical malformations and a predisposition to cancer. Twentyfive percent of patients with DBA have mutations in a gene encoding ribosomal protein S19 (RPS19). Our previous proof-of-concept studies demonstrated that DBA phenotype could be successfully treated using lentiviral vectors in Rps19-deficient DBA mice. In our present study, we developed a clinically applicable single gene, self-inactivating lentiviral vector, containing the human RPS19 cDNA driven by the human elongation factor 1a short promoter, which can be used for clinical gene therapy development for RPS19-deficient DBA. We examined the efficacy and safety of the vector in a Rps19-deficient DBA mouse model and in human primary RPS19-deficient CD34+ cord blood cells. We observed that transduced Rps19-deficient bone marrow cells could reconstitute mice long-term and rescue the bone marrow failure and severe anemia observed in Rps19-deficient mice, with a low risk of mutagenesis and a highly polyclonal insertion site pattern. More importantly, the vector can also rescue impaired erythroid differentiation in human primary RPS19-deficient CD34+ cord blood hematopoietic stem cells. Collectively, our results demonstrate the efficacy and safety of using a clinically applicable lentiviral vector for the successful treatment of Rps19-deficient DBA in a mouse model and in human primary CD34+ cord blood cells. These findings show that this vector can be used to develop clinical gene therapy for RPS19-deficient DBA patients.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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To the university's database
- By the author/editor
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Liu, Yang
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Dahl, Maria
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Debnath, Shubhra ...
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Rothe, Michael
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Smith, Emma
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Tan Grahn, Hooi ...
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show more...
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Warsi, Sarah
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Chen, Jun
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Flygare, Johan
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Schambach, Axel
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Karlsson, Stefan
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Haematologica
- By the university
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Lund University