Optimization of equine infectious anemia derived vectors for hematopoietic cell lineage gene transfer.
Abstract: Gene transfer into hematopoietic cells may allow correction of a variety of hematopoietic and metabolic disorders. Optimized HIV-1 based lentiviral vectors have been developed for improved gene transfer and transgene expression into hematopoietic cells. However, the use of HIV-1 based vectors for human gene therapy may be limited due to ethical and biosafety issues. We report that vectors based on the non-primate equine infectious anemia virus (EIAV) transduce a variety of human hematopoietic cell lines and primary blood cells. To investigate optimization of gene expression in hematopoietic cells, we compared a variety of post-transcriptional elements and promoters in the context of EIAV vectors. We observed cell specific increase in the number of transgene expressing cells with the different post-transcriptional elements, whereas the use of elongation factor alpha 1 (EFalpha1) promoter resulted in significant increases in both the number of transgene expressing cells and the level of transgene protein in all cell types tested. We then demonstrate increased transduction of hematopoietic cells using a second-generation EIAV vector containing a self-inactivating EIAV LTR and the EIAV central polypurine tract (cppt). These data suggest that optimized EIAV vectors may be a suitable alternative to HIV-1 vectors for use in hematopoietic gene therapy.
Publication Date: 2004-11-20 PubMed ID: 15550928DOI: 10.1038/sj.gt.3302350Google Scholar: Lookup
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- Journal Article
- Research Support
- U.S. Gov't
- P.H.S.
Summary
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This research mostly focuses on advancing gene transfer into hematopoietic cells with the objective of correcting a range of hematopoietic and metabolic disorders. Utilizing vectors derived from equine infectious anemia virus (EIAV) and optimizing their composition to attain greater transduction efficiency represents the core activity of this study.
Background and Purpose
- The researchers aimed to optimize gene transfer into hematopoietic cells, which could offer potential solutions for various hematopoietic and metabolic disorders.
- EIAV-based vectors were investigated as safer alternatives to HIV-1 vectors, which carry ethical and biosafety concerns if implemented in human gene therapy.
Methodology and Observations
- Human hematopoietic cells were transduced by EIAV vectors and several post-transcriptional elements and promoters were examined to understand their impact on gene expression optimization.
- The researchers observed a cell-specific increase in the number of transgene expressing cells with different post-transcriptional elements.
- Significant boosts in both the quantity of transgene-expressing cells and the transgene protein level were found when the elongation factor alpha 1 (EFalpha1) promoter was used.
Emerging Conclusions
- Following these findings, the team proceeded to enhance the transduction of hematopoietic cells using a second-generation EIAV vector that included a self-inactivating EIAV LTR and the EIAV central polypurine tract (cppt).
- The results suggest that these optimized EIAV vectors may be a sound alternative to HIV-1 vectors for hematopoietic gene therapy.
Implications
- This study offers a valuable addition to research seeking safer vector choices for gene therapy, particularly hematopoietic gene therapy.
- Further research and development could lead to more effective treatments for hematopoietic and metabolic disorders.
Cite This Article
APA
O'Rourke JP, Olsen JC, Bunnell BA.
(2004).
Optimization of equine infectious anemia derived vectors for hematopoietic cell lineage gene transfer.
Gene Ther, 12(1), 22-29.
https://doi.org/10.1038/sj.gt.3302350 Publication
Researcher Affiliations
- Department of Molecular Medicine, Children's Research Institute, Columbus, OH, USA.
MeSH Terms
- Animals
- Cell Line
- Gene Expression
- Genetic Therapy / methods
- Genetic Vectors / administration & dosage
- Hematopoietic Stem Cells
- Humans
- Infectious Anemia Virus, Equine / genetics
- Peptide Elongation Factor 1 / genetics
- Promoter Regions, Genetic
- Transduction, Genetic / methods
- Transgenes
- Virus Inactivation
Grant Funding
- AI47693 / NIAID NIH HHS
- HL10430 / NHLBI NIH HHS
Citations
This article has been cited 8 times.- Munis AM. Gene Therapy Applications of Non-Human Lentiviral Vectors.. Viruses 2020 Sep 29;12(10).
- Ku CA, Pennesi ME. Retinal Gene Therapy: Current Progress and Future Prospects.. Expert Rev Ophthalmol 2015 Jun;10(3):281-299.
- Poeschla E. The importance of becoming double-stranded: Innate immunity and the kinetic model of HIV-1 central plus strand synthesis.. Virology 2013 Jun 20;441(1):1-11.
- Pang HB, Hevroni L, Kol N, Eckert DM, Tsvitov M, Kay MS, Rousso I. Virion stiffness regulates immature HIV-1 entry.. Retrovirology 2013 Jan 10;10:4.
- Durand S, Cimarelli A. The inside out of lentiviral vectors.. Viruses 2011 Feb;3(2):132-159.
- Jacquet BV, Salinas-Mondragon R, Liang H, Therit B, Buie JD, Dykstra M, Campbell K, Ostrowski LE, Brody SL, Ghashghaei HT. FoxJ1-dependent gene expression is required for differentiation of radial glia into ependymal cells and a subset of astrocytes in the postnatal brain.. Development 2009 Dec;136(23):4021-31.
- Jacquet BV, Patel M, Iyengar M, Liang H, Therit B, Salinas-Mondragon R, Lai C, Olsen JC, Anton ES, Ghashghaei HT. Analysis of neuronal proliferation, migration and differentiation in the postnatal brain using equine infectious anemia virus-based lentiviral vectors.. Gene Ther 2009 Aug;16(8):1021-33.
- Langelier CR, Sandrin V, Eckert DM, Christensen DE, Chandrasekaran V, Alam SL, Aiken C, Olsen JC, Kar AK, Sodroski JG, Sundquist WI. Biochemical characterization of a recombinant TRIM5alpha protein that restricts human immunodeficiency virus type 1 replication.. J Virol 2008 Dec;82(23):11682-94.
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