title: Safety and biodistribution assessment of sc-rAAV2.5IL-1Ra administered via intra-articular injection in a mono-iodoacetate-induced osteoarthritis rat model.
abstract: Interleukin-1 (IL-1) plays an important role in the pathophysiology of osteoarthritis (OA), and gene transfer of IL-1 receptor antagonist (IL-1Ra) holds promise for OA treatment. A preclinical safety and biodistribution study evaluated a self-complementary adeno-associated viral vector carrying rat IL-1Ra transgene (sc-rAAV2.5rIL-1Ra) at 5 × 10(8), 5 × 10(9), or 5 × 10(10) vg/knee, or human IL-1Ra transgene (sc-rAAV2.5hIL-1Ra) at 5 × 10(10) vg/knee, in Wistar rats with mono-iodoacetate (MIA)-induced OA at days 7, 26, 91, 180, and 364 following intra-articular injection. The MIA-induced OA lesions were consistent with the published data on this model. The vector genomes persisted in the injected knees for up to a year with only limited vector leakage to systemic circulation and uptake in tissues outside the knee. Low levels of IL-1Ra expression and mitigation of OA lesions were observed in the vector-injected knees, albeit inconsistently. Neutralizing antibodies against the vector capsid developed in a dose-dependent manner, but only the human vector induced a small splenic T-cell immune response to the vector capsid. No local or systemic toxicity attributable to vector administration was identified in the rats as indicated by clinical signs, body weight, feed consumption, clinical pathology, and gross and microscopic pathology through day 364. Taken together, the gene therapy vector demonstrated a favorable safety profile.
authors.affiliation: Applied Toxicology and Gene Therapy Pharmacology/Toxicology Program, Lovelace Respiratory Research Institute , Albuquerque, New Mexico, USA.
authors.forename: Gensheng
authors.initials: G
authors.lastname: Wang
authors.affiliation: Rehabilitation Medicine Research Center, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Evans
authors.affiliation: Applied Toxicology and Gene Therapy Pharmacology/Toxicology Program, Lovelace Respiratory Research Institute , Albuquerque, New Mexico, USA.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Benson
authors.affiliation: Applied Toxicology and Gene Therapy Pharmacology/Toxicology Program, Lovelace Respiratory Research Institute , Albuquerque, New Mexico, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hutt
authors.affiliation: Applied Toxicology and Gene Therapy Pharmacology/Toxicology Program, Lovelace Respiratory Research Institute , Albuquerque, New Mexico, USA.
authors.forename: JeanClare
authors.initials: J
authors.lastname: Seagrave
authors.affiliation: Applied Toxicology and Gene Therapy Pharmacology/Toxicology Program, Lovelace Respiratory Research Institute , Albuquerque, New Mexico, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Wilder
authors.affiliation: Gene Therapy Center, University of North Carolina , Chapel Hill, North Carolina, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Grieger
authors.affiliation: Gene Therapy Center, University of North Carolina , Chapel Hill, North Carolina, USA.
authors.forename: R Jude
authors.initials: RJ
authors.lastname: Samulski
authors.affiliation: Division of Pre-Clinical Innovations, National Center for Advancing Translational Sciences, NIH , Bethesda, Maryland, USA.
authors.forename: Pramod S
authors.initials: PS
authors.lastname: Terse
references.citation: Hum Gene Ther. 2009 Feb;20(2):97-101
references.pmid: 18986219
references.citation: Best Pract Res Clin Rheumatol. 2008 Apr;22(2):351-84
references.pmid: 18455690
references.citation: Osteoarthritis Cartilage. 2010 Oct;18 Suppl 3:S24-34
references.pmid: 20864021
references.citation: J Gene Med. 2009 Jul;11(7):605-14
references.pmid: 19384892
references.citation: Arthritis Rheum. 1996 Sep;39(9):1535-44
references.pmid: 8814066
references.citation: Arthritis Rheum. 2009 Mar 15;61(3):344-52
references.pmid: 19248129
references.citation: PM R. 2011 Jun;3(6 Suppl 1):S3-11
references.pmid: 21703577
references.citation: Arthritis Res Ther. 2014;16(5):470
references.pmid: 25606597
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8698-703
references.pmid: 15939878
references.citation: Arthritis Rheum. 2008 Jan;58(1):26-35
references.pmid: 18163497
references.citation: J Orthop Res. 2004 Jul;22(4):726-34
references.pmid: 15183427
references.citation: Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10764-8
references.pmid: 8248169
references.citation: Blood. 2003 Jul 15;102(2):480-8
references.pmid: 12637328
references.citation: Mol Ther Methods Clin Dev. 2014 Jun 11;1:14018
references.pmid: 26015962
references.citation: Gene Ther. 2013 Jun;20(6):670-7
references.pmid: 23151520
references.citation: Gene Ther. 2002 Jan;9(1):12-20
references.pmid: 11850718
references.citation: J Bone Joint Surg Am. 1971 Apr;53(3):523-37
references.pmid: 5580011
references.citation: Toxicol Pathol. 2003 Nov-Dec;31(6):619-24
references.pmid: 14585729
references.citation: Arthritis Rheum. 1997 Jun;40(6):1012-9
references.pmid: 9182910
references.citation: J Orthop Res. 2004 Jul;22(4):742-50
references.pmid: 15183429
references.citation: Arthritis Rheum. 1997 Sep;40(9):1670-9
references.pmid: 9324022
references.citation: Osteoarthritis Cartilage. 2004 Apr;12(4):284-95
references.pmid: 15023380
references.citation: Nat Rev Rheumatol. 2014 Jan;10(1):11-22
references.pmid: 24189839
references.citation: Hum Gene Ther. 2011 Feb;22(2):155-65
references.pmid: 20812844
references.citation: Skeletal Radiol. 2001 Mar;30(3):144-50
references.pmid: 11357452