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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.
Hum Gene Ther Clin Dev 2017; 28(3):145-156HG

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.

Authors+Show Affiliations

1 Department of Physiology, Johns Hopkins University , Baltimore, Maryland.2 Lovelace Respiratory Research Institute , Albuquerque, New Mexico.2 Lovelace Respiratory Research Institute , Albuquerque, New Mexico.3 Department of Anatomy and Cell Biology, University of Iowa , Iowa City, Iowa.3 Department of Anatomy and Cell Biology, University of Iowa , Iowa City, Iowa.4 Department of Microbiology & Physiological Systems, University of Massachusetts , Worcester, Massachusetts.5 Department of Pediatrics, University of Florida , Gainesville, Florida.6 Department of Medicine, Johns Hopkins University , Baltimore, Maryland.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28726496

Citation

Guggino, William B., et al. "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, no. 3, 2017, pp. 145-156.
Guggino WB, Benson J, Seagrave J, et al. 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. Hum Gene Ther Clin Dev. 2017;28(3):145-156.
Guggino, W. B., Benson, J., Seagrave, J., Yan, Z., Engelhardt, J., Gao, G., ... Cebotaru, L. (2017). 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, 28(3), pp. 145-156. doi:10.1089/humc.2017.067.
Guggino WB, et al. 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. Hum Gene Ther Clin Dev. 2017;28(3):145-156. PubMed PMID: 28726496.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Guggino,William B, AU - Benson,Janet, AU - Seagrave,JeanClare, AU - Yan,Ziying, AU - Engelhardt,John, AU - Gao,Guangping, AU - Conlon,Thomas J, AU - Cebotaru,Liudmila, Y1 - 2017/07/19/ PY - 2017/7/21/pubmed PY - 2018/1/13/medline PY - 2017/7/21/entrez KW - AAV1 KW - AAV5 KW - cystic fibrosis KW - lung KW - rhesus SP - 145 EP - 156 JF - Human gene therapy. Clinical development JO - Hum Gene Ther Clin Dev VL - 28 IS - 3 N2 - 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. SN - 2324-8645 UR - https://www.unboundmedicine.com/medline/citation/28726496/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_ L2 - https://www.liebertpub.com/doi/full/10.1089/humc.2017.067?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -