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Correction of SCID-X1 using an enhancerless Vav promoter.
Hum Gene Ther. 2011 Mar; 22(3):263-70.HG

Abstract

The efficacy of gene therapy for the treatment of inherited immunodeficiency has been highlighted in recent clinical trials, although in some cases complicated by insertional mutagenesis and silencing of vector genomes through methylation. To minimize these effects, we have evaluated the use of regulatory elements that confer reliability of gene expression, but also lack potent indiscriminate enhancer activity. The Vav1 proximal promoter is particularly attractive in this regard and may be useful in situations where high-level or complex regulation of gene expression is not necessary. X-linked severe combined immunodeficiency (SCID-X1) is a good candidate for such an approach, particularly as there may be additional disease-related intrinsic risks of leukemogenesis, and where safety is therefore a paramount concern. We have tested whether lentiviral vectors expressing the common cytokine receptor gamma chain under the control of the proximal Vav1 gene promoter are effective for correction of signaling defects and the disease phenotype. Despite low-level gene expression, we observed near-complete restoration of cytokine-mediated STAT5 phosphorylation in a model cell line. Furthermore, at low vector copy number, highly effective T- and B-lymphocyte reconstitution was achieved in vivo in a murine model of SCID-X1, in both primary and secondary graft recipients. This vector configuration deserves further evaluation and consideration for future clinical trials.

Authors+Show Affiliations

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas y Centro de Investigación Biomédica en Red de Enfermedades Raras, 28040 Madrid, España.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20887212

Citation

Almarza, E, et al. "Correction of SCID-X1 Using an Enhancerless Vav Promoter." Human Gene Therapy, vol. 22, no. 3, 2011, pp. 263-70.
Almarza E, Zhang F, Santilli G, et al. Correction of SCID-X1 using an enhancerless Vav promoter. Hum Gene Ther. 2011;22(3):263-70.
Almarza, E., Zhang, F., Santilli, G., Blundell, M. P., Howe, S. J., Thornhill, S. I., Bueren, J. A., & Thrasher, A. J. (2011). Correction of SCID-X1 using an enhancerless Vav promoter. Human Gene Therapy, 22(3), 263-70. https://doi.org/10.1089/hum.2010.119
Almarza E, et al. Correction of SCID-X1 Using an Enhancerless Vav Promoter. Hum Gene Ther. 2011;22(3):263-70. PubMed PMID: 20887212.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Correction of SCID-X1 using an enhancerless Vav promoter. AU - Almarza,E, AU - Zhang,F, AU - Santilli,G, AU - Blundell,M P, AU - Howe,S J, AU - Thornhill,S I, AU - Bueren,J A, AU - Thrasher,A J, Y1 - 2011/02/07/ PY - 2010/10/5/entrez PY - 2010/10/5/pubmed PY - 2011/6/22/medline SP - 263 EP - 70 JF - Human gene therapy JO - Hum. Gene Ther. VL - 22 IS - 3 N2 - The efficacy of gene therapy for the treatment of inherited immunodeficiency has been highlighted in recent clinical trials, although in some cases complicated by insertional mutagenesis and silencing of vector genomes through methylation. To minimize these effects, we have evaluated the use of regulatory elements that confer reliability of gene expression, but also lack potent indiscriminate enhancer activity. The Vav1 proximal promoter is particularly attractive in this regard and may be useful in situations where high-level or complex regulation of gene expression is not necessary. X-linked severe combined immunodeficiency (SCID-X1) is a good candidate for such an approach, particularly as there may be additional disease-related intrinsic risks of leukemogenesis, and where safety is therefore a paramount concern. We have tested whether lentiviral vectors expressing the common cytokine receptor gamma chain under the control of the proximal Vav1 gene promoter are effective for correction of signaling defects and the disease phenotype. Despite low-level gene expression, we observed near-complete restoration of cytokine-mediated STAT5 phosphorylation in a model cell line. Furthermore, at low vector copy number, highly effective T- and B-lymphocyte reconstitution was achieved in vivo in a murine model of SCID-X1, in both primary and secondary graft recipients. This vector configuration deserves further evaluation and consideration for future clinical trials. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/20887212/Correction_of_SCID_X1_using_an_enhancerless_Vav_promoter_ L2 - https://www.liebertpub.com/doi/full/10.1089/hum.2010.119?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -