Development of a forward-oriented therapeutic lentiviral vector for hemoglobin disorders

Naoya Uchida (), Matthew M. Hsieh, Lydia Raines, Juan J. Haro-Mora, Selami Demirci, Aylin C. Bonifacino, Allen E. Krouse, Mark E. Metzger, Robert E. Donahue and John F. Tisdale
Additional contact information
Naoya Uchida: National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)
Matthew M. Hsieh: National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)
Lydia Raines: National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)
Juan J. Haro-Mora: National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)
Selami Demirci: National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)
Aylin C. Bonifacino: NHLBI, NIH
Allen E. Krouse: NHLBI, NIH
Mark E. Metzger: NHLBI, NIH
Robert E. Donahue: National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)
John F. Tisdale: National Heart Lung and Blood Institute (NHLBI), National Institutes of Health (NIH)

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Hematopoietic stem cell (HSC) gene therapy is being evaluated for hemoglobin disorders including sickle cell disease (SCD). Therapeutic globin vectors have demanding requirements including high-efficiency transduction at the HSC level and high-level, erythroid-specific expression with long-term persistence. The requirement of intron 2 for high-level β-globin expression dictates a reverse-oriented globin-expression cassette to prevent its loss from RNA splicing. Current reverse-oriented globin vectors can drive phenotypic correction, but they are limited by low vector titers and low transduction efficiencies. Here we report a clinically relevant forward-oriented β-globin-expressing vector, which has sixfold higher vector titers and four to tenfold higher transduction efficiency for long-term hematopoietic repopulating cells in humanized mice and rhesus macaques. Insertion of Rev response element (RRE) allows intron 2 to be retained, and β-globin production is observed in transplanted macaques and human SCD CD34+ cells. These findings bring us closer to a widely applicable gene therapy for hemoglobin disorders.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-12456-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12456-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-12456-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().