Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene

J M Staber; M J Pollpeter; C-G Anderson; M Burrascano; A L Cooney; P L Sinn; D T Rutkowski; W C Raschke; P B McCray

doi:10.1038/gt.2017.67

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Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene

Journal article

Peer reviewed

Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene

J M Staber, M J Pollpeter, C-G Anderson, M Burrascano, A L Cooney, P L Sinn, D T Rutkowski, W C Raschke and P B McCray

Gene therapy, Vol.24(11), pp.742-748

11/2017

DOI: 10.1038/gt.2017.67

PMCID: PMC5937993

PMID: 28905885

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https://www.ncbi.nlm.nih.gov/pmc/articles/5937993View

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Abstract

Current therapies for hemophilia A include frequent prophylactic or on-demand intravenous factor treatments which are costly, inconvenient and may lead to inhibitor formation. Viral vector delivery of factor VIII (FVIII) cDNA has the potential to alleviate the debilitating clotting defects. Lentiviral-based vectors delivered to murine models of hemophilia A mediate phenotypic correction. However, a limitation of lentiviral-mediated FVIII delivery is inefficient transduction of target cells. Here, we engineer a feline immunodeficiency virus (FIV) -based lentiviral vector pseudotyped with the baculovirus GP64 envelope glycoprotein to mediate efficient gene transfer to mouse hepatocytes. In anticipation of future studies in FVIII-deficient dogs, we investigated the efficacy of FIV-delivered canine FVIII (cFVIII). Codon-optimization of the cFVIII sequence increased activity and decreased blood loss as compared to the native sequence. Further, we compared a standard B-domain deleted FVIII cDNA to a cDNA including 256 amino acids of the B-domain with 11 potential asparagine-linked oligosaccharide linkages. Restoring a partial B-domain resulted in modest reduction of endoplasmic reticulum (ER) stress markers. Importantly, our optimized vectors achieved wild-type levels of phenotypic correction with minimal inhibitor formation. These studies provide insights into optimal design of a therapeutically relevant gene therapy vector for a devastating bleeding disorder.

Details

Title: Subtitle: Long-term correction of hemophilia A mice following lentiviral mediated delivery of an optimized canine factor VIII gene
Creators: J M Staber - Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA
M J Pollpeter - Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA, USA
C-G Anderson - Department of Virogenics, San Diego, CA, USA
M Burrascano - Department of Virogenics, San Diego, CA, USA
A L Cooney - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
P L Sinn - Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases, Iowa City, IA, USA
D T Rutkowski - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
W C Raschke - Department of Virogenics, San Diego, CA, USA
P B McCray - Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Gene therapy, Vol.24(11), pp.742-748
DOI: 10.1038/gt.2017.67
PMID: 28905885
PMCID: PMC5937993
NLM abbreviation: Gene Ther
ISSN: 0969-7128
eISSN: 1476-5462
Publisher: England
Language: English
Date published: 11/2017
Academic Unit: Microbiology and Immunology; Pulmonary Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Hematology/Oncology; Internal Medicine
Record Identifier: 9984070360302771

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