title: scAAVIL-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy.
abstract: A gene therapeutic approach to treat osteoarthritis (OA) appears to be on the horizon for millions of people who suffer from this disease. Previously we described optimization of a scAAVIL-1ra gene therapeutic vector and initially tested this in an equine model verifying long-term intrasynovial IL-1ra protein at therapeutic levels. Using this vector, we carried out a dosing trial in six horses to verify protein levels and establish a dose that would express relevant levels of therapeutic protein for extended periods of time (8 months). A novel arthroscopic procedure used to detect green fluorescence protein (GFP) fluorescence intrasynovially confirmed successful transduction of the scAAVGFP vector in both the synovial and cartilage tissues. No evidence of intra-articular toxicity was detected. Immune responses to vector revealed development of neutralizing antibodies (Nabs) within 2 weeks of administration, which persisted for the duration of the study but did not lower protein expression intra-articularly. Re-dosing with a different serotype to attain therapeutic levels of protein confirmed establishment of successful transduction. This is the first study in an equine model to establish a dosing/redosing protocol, as well as examine the Nab response to capsid and supports further clinical investigation to determine the clinical efficacy of scAAVIL-1ra to treat OA.
authors.affiliation: Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.
authors.forename: L R
authors.initials: LR
authors.lastname: Goodrich
authors.affiliation: UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Grieger
authors.affiliation: Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Phillips
authors.affiliation: UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: N
authors.initials: N
authors.lastname: Khan
authors.affiliation: UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Gray
authors.affiliation: Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: McIlwraith
authors.affiliation: UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Samulski
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D050824:Carpal Joints / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D015870:Gene Expression / Q000276:immunology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D006736:Horses; D053590:Interleukin 1 Receptor Antagonist Protein / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D010003:Osteoarthritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D013583:Synovial Membrane / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D053590:Interleukin 1 Receptor Antagonist Protein