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Suwanmanee T, Ferris MT, Hu P, et al. Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery. Mol Ther Methods Clin Dev. 2017;5:83-92doi: 10.1016/j.omtm.2017.03.009.
Suwanmanee, T., Ferris, M. T., Hu, P., Gui, T., Montgomery, S. A., Pardo-Manuel de Villena, F., & Kafri, T. (2017). Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery. Molecular therapy. Methods & clinical development, 583-92. https://doi.org/10.1016/j.omtm.2017.03.009
Suwanmanee, Thipparat, et al. "Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery." Molecular therapy. Methods & clinical development vol. 5 (2017): 83-92. doi: https://doi.org/10.1016/j.omtm.2017.03.009
Suwanmanee T, Ferris MT, Hu P, Gui T, Montgomery SA, Pardo-Manuel de Villena F, Kafri T. Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery. Mol Ther Methods Clin Dev. 2017 Apr 05;5:83-92. doi: 10.1016/j.omtm.2017.03.009. eCollection 2017 Jun 16. PMID: 28480308; PMCID: PMC5415322.
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Mol Ther Methods Clin Dev. 2017 Apr 05;5:83-92. doi: 10.1016/j.omtm.2017.03.009. eCollection 2017 Jun 16.

Toward Personalized Gene Therapy: Characterizing the Host Genetic Control of Lentiviral-Vector-Mediated Hepatic Gene Delivery.

Molecular therapy. Methods & clinical development

Thipparat Suwanmanee, Martin T Ferris, Peirong Hu, Tong Gui, Stephanie A Montgomery, Fernando Pardo-Manuel de Villena, Tal Kafri

Affiliations

  1. Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  2. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  4. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  5. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

PMID: 28480308 PMCID: PMC5415322 DOI: 10.1016/j.omtm.2017.03.009

Abstract

The success of lentiviral vectors in curing fatal genetic and acquired diseases has opened a new era in human gene therapy. However, variability in the efficacy and safety of this therapeutic approach has been reported in human patients. Consequently, lentiviral-vector-based gene therapy is limited to incurable human diseases, with little understanding of the underlying causes of adverse effects and poor efficacy. To assess the role that host genetic variation has on efficacy of gene therapy, we characterized lentiviral-vector gene therapy within a set of 12 collaborative cross mouse strains. Lentiviral vectors carrying the firefly luciferase cDNA under the control of a liver-specific promoter were administered to female mice, with total-body and hepatic luciferase expression periodically monitored through 41 weeks post-vector administration. Vector copy number per diploid genome in mouse liver and spleen was determined at the end of this study. We identified major strain-specific contributions to overall success of transduction, vector biodistribution, maximum luciferase expression, and the kinetics of luciferase expression throughout the study. Our results highlight the importance of genetic variation on gene-therapeutic efficacy; provide new models with which to more rigorously assess gene therapy approaches; and suggest that redesigning preclinical studies of gene-therapy methodologies might be appropriate.

Keywords: collaborative cross; gene therapy; heritability; lentivirus; mouse

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