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Safety of liver gene transfer following peripheral intravascular delivery of adeno-associated virus (AAV)-5 and AAV-6 in a large animal model.
Hum Gene Ther 2011; 22(7):843-52HG

Abstract

Intravascular delivery of adeno-associated virus (AAV) vector is commonly used for liver-directed gene therapy. In humans, the high prevalence of neutralizing antibodies to AAV-2 capsid and the wide cross-reactivity with other serotypes hamper vector transduction efficacy. Moreover, the safety of gene-based approaches depends on vector biodistribution, vector dose, and route of administration. Here we sought to characterize the safety of AAV-5 and AAV-6 for liver-mediated human factor IX (hFIX) expression in rabbits at doses of 1 × 10(12) or 1 × 10(13) viral genomes/kg. Circulating therapeutic levels of FIX were observed in both cohorts of AAV-6-hFIX, whereas for AAV-5-hFIX only the high dose was effective. Long-lasting inhibitory antibodies to hFIX were detected in three of the 10 AAV-6-injected animals but were absent in the AAV-5 group. Overall, vector shedding in the semen was transient and vector dose-dependent. However, the kinetics of clearance were remarkably faster for AAV-5 (3-5 weeks) compared with AAV-6 (10-13 weeks). AAV-6 vector sequences outside the liver were minimal at 20-30 weeks post-injection. In contrast, AAV-5 exhibited relatively high amounts of vector DNA in tissues other than the liver. Together these data are useful to further define the safety and potential for clinical translation of these AAV vectors.

Authors+Show Affiliations

The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21126217

Citation

Favaro, Patricia, et al. "Safety of Liver Gene Transfer Following Peripheral Intravascular Delivery of Adeno-associated Virus (AAV)-5 and AAV-6 in a Large Animal Model." Human Gene Therapy, vol. 22, no. 7, 2011, pp. 843-52.
Favaro P, Finn JD, Siner JI, et al. Safety of liver gene transfer following peripheral intravascular delivery of adeno-associated virus (AAV)-5 and AAV-6 in a large animal model. Hum Gene Ther. 2011;22(7):843-52.
Favaro, P., Finn, J. D., Siner, J. I., Wright, J. F., High, K. A., & Arruda, V. R. (2011). Safety of liver gene transfer following peripheral intravascular delivery of adeno-associated virus (AAV)-5 and AAV-6 in a large animal model. Human Gene Therapy, 22(7), pp. 843-52. doi:10.1089/hum.2010.155.
Favaro P, et al. Safety of Liver Gene Transfer Following Peripheral Intravascular Delivery of Adeno-associated Virus (AAV)-5 and AAV-6 in a Large Animal Model. Hum Gene Ther. 2011;22(7):843-52. PubMed PMID: 21126217.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Safety of liver gene transfer following peripheral intravascular delivery of adeno-associated virus (AAV)-5 and AAV-6 in a large animal model. AU - Favaro,Patricia, AU - Finn,Jonathan D, AU - Siner,Joshua I, AU - Wright,J Fraser, AU - High,Katherine A, AU - Arruda,Valder R, Y1 - 2011/03/08/ PY - 2010/12/4/entrez PY - 2010/12/4/pubmed PY - 2011/12/13/medline SP - 843 EP - 52 JF - Human gene therapy JO - Hum. Gene Ther. VL - 22 IS - 7 N2 - Intravascular delivery of adeno-associated virus (AAV) vector is commonly used for liver-directed gene therapy. In humans, the high prevalence of neutralizing antibodies to AAV-2 capsid and the wide cross-reactivity with other serotypes hamper vector transduction efficacy. Moreover, the safety of gene-based approaches depends on vector biodistribution, vector dose, and route of administration. Here we sought to characterize the safety of AAV-5 and AAV-6 for liver-mediated human factor IX (hFIX) expression in rabbits at doses of 1 × 10(12) or 1 × 10(13) viral genomes/kg. Circulating therapeutic levels of FIX were observed in both cohorts of AAV-6-hFIX, whereas for AAV-5-hFIX only the high dose was effective. Long-lasting inhibitory antibodies to hFIX were detected in three of the 10 AAV-6-injected animals but were absent in the AAV-5 group. Overall, vector shedding in the semen was transient and vector dose-dependent. However, the kinetics of clearance were remarkably faster for AAV-5 (3-5 weeks) compared with AAV-6 (10-13 weeks). AAV-6 vector sequences outside the liver were minimal at 20-30 weeks post-injection. In contrast, AAV-5 exhibited relatively high amounts of vector DNA in tissues other than the liver. Together these data are useful to further define the safety and potential for clinical translation of these AAV vectors. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/21126217/Safety_of_liver_gene_transfer_following_peripheral_intravascular_delivery_of_adeno_associated_virus__AAV__5_and_AAV_6_in_a_large_animal_model_ L2 - https://www.liebertpub.com/doi/full/10.1089/hum.2010.155?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -