Journal article
A Preclinical Study in Rhesus Macaques for Cystic Fibrosis to Assess Gene Transfer and Transduction by AAV1 and AAV5 with a Dual-Luciferase Reporter System
Human gene therapy. Clinical development, Vol.28(3), pp.145-156
09/01/2017
DOI: 10.1089/humc.2017.067
PMCID: PMC5655841
PMID: 28726496
Abstract
Cystic fibrosis (CF) is an autosomal recessive disease that is potentially treatable by gene therapy. Since the identification of the gene encoding CF transmembrane conductance regulator, a number of preclinical and clinical trials have been conducted using the first generation of adeno-associated virus, AAV2. All these studies showed that AAV gene therapy for CF is safe, but clinical benefit was not clearly demonstrated. Thus, a new generation of AAV vectors based on other serotypes is needed to move the field forward. This study tested two AAV serotypes (AAV1 and AAV5) using a dual-luciferase reporter system with firefly and
Renilla
luciferase genes packaged into AAV1 or AAV5, respectively. Two male and two female Rhesus macaques were each instilled in their lungs with both serotypes using a Penn-Century microsprayer. Both AAV1 and AAV5 vector genomes were detected in all the lung samples when measured at the time of necropsy, 45 days after instillation. However, the vector genome number for AAV1 was at least 10-fold higher than for AAV5. Likewise, luciferase activity was also detected in the same samples at 45 days. AAV1-derived activity was not statistically greater than that derived from AAV5. These data suggest that gene transfer is greater for AAV1 than for AAV5 in macaque lungs. Serum neutralizing antibodies were increased dramatically against both serotypes but were less abundant with AAV1 than with AAV5. No adverse events were noted, again indicating that AAV gene therapy is safe. These results suggest that with more lung-tropic serotypes such as AAV1, new clinical studies of gene therapy using AAV are warranted.
Details
- Title: Subtitle
- A Preclinical Study in Rhesus Macaques for Cystic Fibrosis to Assess Gene Transfer and Transduction by AAV1 and AAV5 with a Dual-Luciferase Reporter System
- Creators
- William B Guggino - 1Department of Physiology, Johns Hopkins University, Baltimore, MarylandJanet Benson - 2Lovelace Respiratory Research Institute, Albuquerque, New MexicoJeanClare Seagrave - 2Lovelace Respiratory Research Institute, Albuquerque, New MexicoZiying Yan - 3Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IowaJohn Engelhardt - 3Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IowaGuangping Gao - 4Department of Microbiology & Physiological Systems, University of Massachusetts, Worcester, MassachusettsThomas J Conlon - 5Department of Pediatrics, University of Florida, Gainesville, FloridaLiudmila Cebotaru - 6Department of Medicine, Johns Hopkins University, Baltimore, Maryland
- Resource Type
- Journal article
- Publication Details
- Human gene therapy. Clinical development, Vol.28(3), pp.145-156
- DOI
- 10.1089/humc.2017.067
- PMID
- 28726496
- PMCID
- PMC5655841
- NLM abbreviation
- Hum Gene Ther Clin Dev
- ISSN
- 2324-8637
- eISSN
- 2324-8645
- Publisher
- Mary Ann Liebert, Inc
- Language
- English
- Date published
- 09/01/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984025415002771
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