Inflammation and immune response of intra-articular serotype 2 adeno-associated virus or adenovirus vectors in a large animal model.
Abstract: Intra-articular gene therapy has potential for the treatment of osteoarthritis and rheumatoid arthritis. To quantify in vitro relative gene transduction, equine chondrocytes and synovial cells were treated with adenovirus vectors (Ad), serotype 2 adeno-associated virus vectors (rAAV2), or self-complementary (sc) AAV2 vectors carrying green fluorescent protein (GFP). Using 6 horses, bilateral metacarpophalangeal joints were injected with Ad, rAAV2, or scAAV2 vectors carrying GFP genes to assess the in vivo joint inflammation and neutralizing antibody (NAb) titer in serum and joint fluid. In vitro, the greater transduction efficiency and sustained gene expression were achieved by scAAV2 compared to rAAV2 in equine chondrocytes and synovial cells. In vivo, AAV2 demonstrated less joint inflammation than Ad, but similar NAb titer. The scAAV2 vectors can induce superior gene transduction than rAAV2 in articular cells, and both rAAV2 and scAAV2 vectors were showed to be safer for intra-articular use than Ad vectors.
Publication Date: 2012-01-11 PubMed ID: 22288012PubMed Central: PMC3263587DOI: 10.1155/2012/735472Google Scholar: Lookup
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- Journal Article
Summary
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This study explores the potential of intra-articular gene therapy for the treatment of osteoarthritis and rheumatoid arthritis. Specifically, the researchers compared the effects of adenovirus vectors, serotype 2 adeno-associated virus vectors, and self-complementary AAV2 vectors on equine cells. They found that scAAV2 demonstrated greater efficiency and persistence, and produced less inflammation than the other vectors, making them a promising avenue for therapeutic use.
Introduction
- The research is centered around testing different methods of intra-articular gene therapy, which is a potential treatment for osteoarthritis and rheumatoid arthritis.
- Intra-articular gene therapy involves injecting genetic material, delivered via a vector like a virus, into the joints affected by the disease.
- The vectors assessed in this study include adenovirus vectors (Ad), serotype 2 adeno-associated virus vectors (rAAV2), and self-complementary (sc) AAV2 vectors – all containing the gene for green fluorescent protein (GFP).
Methods
- The scientists conducted experiments both in vitro (on cells in a controlled laboratory setting) and in vivo (on live horses).
- In the in vitro experiment, equine chondrocytes (cartilage cells) and synovial cells (cells that produce joint fluid) were exposed to the different vectors.
- In the in vivo experiment, the joints of six horses were injected with the three types of vectors.
- The results were analyzed based on the efficiency of gene transduction (how well the GFP gene was taken up and expressed by the cells) and any inflammation or immune response (as measured by neutralizing antibody (NAb) titer in horse’s serum and joint fluid).
Results
- The in vitro experiment showed that the scAAV2 vectors performed the best, achieving more efficient transduction and sustained gene expression.
- Pin vivo, the Ad vectors caused more joint inflammation than the AAV2 vectors. However, the levels of neutralizing antibodies, indicative of an immune response, were similar for the Ad and AAV2 vectors.
Conclusion
- Based on their findings, the researchers concluded that scAAV2 vectors could potentially be superior for intra-articular gene therapy. This is mainly due to their high transduction rates and low inflammation.
- Both rAAV2 and scAAV2 vectors were demonstrated to be safer for intra-articular use than Ad vectors due to causing less inflammation. Hence, using these AAV2-derived vectors could be a more effective approach when developing gene therapies for osteoarthritis and rheumatoid arthritis.
Cite This Article
APA
Ishihara A, Bartlett JS, Bertone AL.
(2012).
Inflammation and immune response of intra-articular serotype 2 adeno-associated virus or adenovirus vectors in a large animal model.
Arthritis, 2012, 735472.
https://doi.org/10.1155/2012/735472 Publication
Researcher Affiliations
- Comparative Orthopedic Research Laboratories, Department of Veterinary Clinical Sciences, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.
Grant Funding
- K08 AR049201 / NIAMS NIH HHS
References
This article includes 29 references
- Lawrence RC, Helmick CG, Arnett FC, Deyo RA, Felson DT, Giannini EH, Heyse SP, Hirsch R, Hochberg MC, Hunder GG, Liang MH, Pillemer SR, Steen VD, Wolfe F. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States.. Arthritis Rheum 1998 May;41(5):778-99.
- Oligino T, Ghivizzani S, Wolfe D, Lechman E, Krisky D, Mi Z, Evans C, Robbins P, Glorioso J. Intra-articular delivery of a herpes simplex virus IL-1Ra gene vector reduces inflammation in a rabbit model of arthritis.. Gene Ther 1999 Oct;6(10):1713-20.
- Kay JD, Gouze E, Oligino TJ, Gouze JN, Watson RS, Levings PP, Bush ML, Dacanay A, Nickerson DM, Robbins PD, Evans CH, Ghivizzani SC. Intra-articular gene delivery and expression of interleukin-1Ra mediated by self-complementary adeno-associated virus.. J Gene Med 2009 Jul;11(7):605-14.
- Bramlage CP, Kaps C, Ungethüm U, Bramlage P, Koziolek M, Wessels J, Krenn V, Pruss A, Müller GA, Strutz F, Burmester GR, Häupl T. Modulatory effects of inflammation and therapy on GDF-5 expression in rheumatoid arthritis synovium.. Scand J Rheumatol 2008 Nov-Dec;37(6):401-9.
- Mease PJ, Hobbs K, Chalmers A, El-Gabalawy H, Bookman A, Keystone E, Furst DE, Anklesaria P, Heald AE. Local delivery of a recombinant adenoassociated vector containing a tumour necrosis factor alpha antagonist gene in inflammatory arthritis: a phase 1 dose-escalation safety and tolerability study.. Ann Rheum Dis 2009 Aug;68(8):1247-54.
- Evans CH, Ghivizzani SC, Robbins PD. Orthopedic gene therapy in 2008.. Mol Ther 2009 Feb;17(2):231-44.
- Roessler BJ, Allen ED, Wilson JM, Hartman JW, Davidson BL. Adenoviral-mediated gene transfer to rabbit synovium in vivo.. J Clin Invest 1993 Aug;92(2):1085-92.
- Ghivizzani SC, Lechman ER, Kang R, Tio C, Kolls J, Evans CH, Robbins PD. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects.. Proc Natl Acad Sci U S A 1998 Apr 14;95(8):4613-8.
- Watanabe S, Imagawa T, Boivin GP, Gao G, Wilson JM, Hirsch R. Adeno-associated virus mediates long-term gene transfer and delivery of chondroprotective IL-4 to murine synovium.. Mol Ther 2000 Aug;2(2):147-52.
- Pan RY, Chen SL, Xiao X, Liu DW, Peng HJ, Tsao YP. Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist.. Arthritis Rheum 2000 Feb;43(2):289-97.
- Ulrich-Vinther M, Duch MR, Søballe K, O'Keefe RJ, Schwarz EM, Pedersen FS. In vivo gene delivery to articular chondrocytes mediated by an adeno-associated virus vector.. J Orthop Res 2004 Jul;22(4):726-34.
- Santangelo KS, Baker SA, Nuovo G, Dyce J, Bartlett JS, Bertone AL. Detectable reporter gene expression following transduction of adenovirus and adeno-associated virus serotype 2 vectors within full-thickness osteoarthritic and unaffected canine cartilage in vitro and unaffected guinea pig cartilage in vivo.. J Orthop Res 2010 Feb;28(2):149-55.
- Jayandharan GR, Zhong L, Li B, Kachniarz B, Srivastava A. Strategies for improving the transduction efficiency of single-stranded adeno-associated virus vectors in vitro and in vivo.. Gene Ther 2008 Sep;15(18):1287-93.
- Goodrich LR, Choi VW, Carbone BA, McIlwraith CW, Samulski RJ. Ex vivo serotype-specific transduction of equine joint tissue by self-complementary adeno-associated viral vectors.. Hum Gene Ther 2009 Dec;20(12):1697-702.
- Ishihara A, Zachos TA, Bartlett JS, Bertone AL. Evaluation of permissiveness and cytotoxic effects in equine chondrocytes, synovial cells, and stem cells in response to infection with adenovirus 5 vectors for gene delivery.. Am J Vet Res 2006 Jul;67(7):1145-55.
- Zachos TA, Shields KM, Bertone AL. Gene-mediated osteogenic differentiation of stem cells by bone morphogenetic proteins-2 or -6.. J Orthop Res 2006 Jun;24(6):1279-91.
- Stachler MD, Chen I, Ting AY, Bartlett JS. Site-specific modification of AAV vector particles with biophysical probes and targeting ligands using biotin ligase.. Mol Ther 2008 Aug;16(8):1467-73.
- Backstrom KC, Bertone AL, Wisner ER, Weisbrode SE. Response of induced bone defects in horses to collagen matrix containing the human parathyroid hormone gene.. Am J Vet Res 2004 Sep;65(9):1223-32.
- Ishihara A, Bertone AL, Rajala-Schultz PJ. Association between subjective lameness grade and kinetic gait parameters in horses with experimentally induced forelimb lameness.. Am J Vet Res 2005 Oct;66(10):1805-15.
- Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.. Methods 2001 Dec;25(4):402-8.
- Betz OB, Betz VM, Nazarian A, Pilapil CG, Vrahas MS, Bouxsein ML, Gerstenfeld LC, Einhorn TA, Evans CH. Direct percutaneous gene delivery to enhance healing of segmental bone defects.. J Bone Joint Surg Am 2006 Feb;88(2):355-65.
- Zaiss AK, Muruve DA. Immune responses to adeno-associated virus vectors.. Curr Gene Ther 2005 Jun;5(3):323-31.
- Mingozzi F, High KA. Immune responses to AAV in clinical trials.. Curr Gene Ther 2007 Oct;7(5):316-24.
- Frank KM, Hogarth DK, Miller JL, Mandal S, Mease PJ, Samulski RJ, Weisgerber GA, Hart J. Investigation of the cause of death in a gene-therapy trial.. N Engl J Med 2009 Jul 9;361(2):161-9.
- Huttner NA, Girod A, Perabo L, Edbauer D, Kleinschmidt JA, Büning H, Hallek M. Genetic modifications of the adeno-associated virus type 2 capsid reduce the affinity and the neutralizing effects of human serum antibodies.. Gene Ther 2003 Dec;10(26):2139-47.
- Gao GP, Alvira MR, Wang L, Calcedo R, Johnston J, Wilson JM. Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy.. Proc Natl Acad Sci U S A 2002 Sep 3;99(18):11854-9.
- Moskalenko M, Chen L, van Roey M, Donahue BA, Snyder RO, McArthur JG, Patel SD. Epitope mapping of human anti-adeno-associated virus type 2 neutralizing antibodies: implications for gene therapy and virus structure.. J Virol 2000 Feb;74(4):1761-6.
- Bragdon B, Bertone AL, Hardy J, Simmons EJ, Weisbrode SE. Use of an isolated joint model to detect early changes induced by intra-articular injection of paclitaxel-impregnated polymeric microspheres.. J Invest Surg 2001 May-Jun;14(3):169-82.
- Kraus VB, Stabler TV, Kong SY, Varju G, McDaniel G. Measurement of synovial fluid volume using urea.. Osteoarthritis Cartilage 2007 Oct;15(10):1217-20.
Citations
This article has been cited 10 times.- Bowlby CM, Purmessur D, Durgam SS. Equine peripheral blood CD14(+) monocyte-derived macrophage in-vitro characteristics after GM-CSF pretreatment and LPS+IFN-γ or IL-4+IL-10 differentiation.. Vet Immunol Immunopathol 2023 Jan;255:110534.
- Thampi P, Samulski RJ, Grieger JC, Phillips JN, McIlwraith CW, Goodrich LR. Gene therapy approaches for equine osteoarthritis.. Front Vet Sci 2022;9:962898.
- Martínez-Hernández E, Zeglin A, Almazan E, Perissinotti P, He Y, Koob M, Martin JL, Piedras-Rentería ES. KLHL1 Controls Ca(V)3.2 Expression in DRG Neurons and Mechanical Sensitivity to Pain.. Front Mol Neurosci 2019;12:315.
- Watson Levings RS, Smith AD, Broome TA, Rice BL, Gibbs EP, Myara DA, Hyddmark EV, Nasri E, Zarezadeh A, Levings PP, Lu Y, White ME, Dacanay EA, Foremny GB, Evans CH, Morton AJ, Winter M, Dark MJ, Nickerson DM, Colahan PT, Ghivizzani SC. Self-Complementary Adeno-Associated Virus-Mediated Interleukin-1 Receptor Antagonist Gene Delivery for the Treatment of Osteoarthritis: Test of Efficacy in an Equine Model.. Hum Gene Ther Clin Dev 2018 Jun;29(2):101-112.
- Goodrich LR, Grieger JC, Phillips JN, Khan N, Gray SJ, McIlwraith CW, Samulski RJ. scAAVIL-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy.. Gene Ther 2015 Jul;22(7):536-45.
- Wilson CG, Martín-Saavedra FM, Padilla F, Fabiilli ML, Zhang M, Baez AM, Bonkowski CJ, Kripfgans OD, Voellmy R, Vilaboa N, Fowlkes JB, Franceschi RT. Patterning expression of regenerative growth factors using high intensity focused ultrasound.. Tissue Eng Part C Methods 2014 Oct;20(10):769-79.
- Wilson CG, Martín-Saavedra FM, Vilaboa N, Franceschi RT. Advanced BMP gene therapies for temporal and spatial control of bone regeneration.. J Dent Res 2013 May;92(5):409-17.
- Goodrich LR, Phillips JN, McIlwraith CW, Foti SB, Grieger JC, Gray SJ, Samulski RJ. Optimization of scAAVIL-1ra In Vitro and In Vivo to Deliver High Levels of Therapeutic Protein for Treatment of Osteoarthritis.. Mol Ther Nucleic Acids 2013 Feb 5;2(2):e70.
- Evans CH, Ghivizzani SC, Robbins PD. Arthritis gene therapy and its tortuous path into the clinic.. Transl Res 2013 Apr;161(4):205-16.
- Watson RS, Broome TA, Levings PP, Rice BL, Kay JD, Smith AD, Gouze E, Gouze JN, Dacanay EA, Hauswirth WW, Nickerson DM, Dark MJ, Colahan PT, Ghivizzani SC. scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints.. Gene Ther 2013 Jun;20(6):670-7.
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