FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Front Vet Sci / Gene therapy approaches for equine osteoarthritis.
Frontiers in veterinary science2022; 9; 962898; doi: 10.3389/fvets.2022.962898

Gene therapy approaches for equine osteoarthritis.

Abstract: With an intrinsically low ability for self-repair, articular cartilage injuries often progress to cartilage loss and joint degeneration resulting in osteoarthritis (OA). Osteoarthritis and the associated articular cartilage changes can be debilitating, resulting in lameness and functional disability both in human and equine patients. While articular cartilage damage plays a central role in the pathogenesis of OA, the contribution of other joint tissues to the pathogenesis of OA has increasingly been recognized thus prompting a whole organ approach for therapeutic strategies. Gene therapy methods have generated significant interest in OA therapy in recent years. These utilize viral or non-viral vectors to deliver therapeutic molecules directly into the joint space with the goal of reprogramming the cells' machinery to secrete high levels of the target protein at the site of injection. Several viral vector-based approaches have demonstrated successful gene transfer with persistent therapeutic levels of transgene expression in the equine joint. As an experimental model, horses represent the pathology of human OA more accurately compared to other animal models. The anatomical and biomechanical similarities between equine and human joints also allow for the use of similar imaging and diagnostic methods as used in humans. In addition, horses experience naturally occurring OA and undergo similar therapies as human patients and, therefore, are a clinically relevant patient population. Thus, further studies utilizing this equine model would not only help advance the field of human OA therapy but also benefit the clinical equine patients with naturally occurring joint disease. In this review, we discuss the advancements in gene therapeutic approaches for the treatment of OA with the horse as a relevant patient population as well as an effective and commonly utilized species as a translational model.
Copyright © 2022 Thampi, Samulski, Grieger, Phillips, McIlwraith and Goodrich.
Get Full Text
Publication Date: 2022-09-28 PubMed ID: 36246316PubMed Central: PMC9558289DOI: 10.3389/fvets.2022.962898Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Review

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research article’s abstract looks at how gene therapy methods can potentially be used to treat osteoarthritis (OA), a degenerative condition affecting the joints, in horses and potentially in humans. The study highlights horses as a clinically relevant model for exploring these gene therapy approaches due to the similarities between equine and human joints, both anatomically and biomechanically.

Introduction to Osteoarthritis and the Need for New Therapies

  • Osteoarthritis (OA) is a chronic disease characterized by the degeneration of articular cartilage, leading to pain and disability. In both humans and horses, these cartilage injuries often progress to cartilage loss and joint degeneration.
  • Despite its prevalence, the self-repair ability of articular cartilage is intrinsically low. This makes treatments very difficult and highlights the need for innovative therapeutic methods.

Gene Therapy: A New Approach to Osteoarthritis Treatment

  • Recently, gene therapy methods have attracted attention as a potential treatment for OA. These techniques involve using viral or non-viral vectors to deliver therapeutic molecules into the joint space directly. This process aims to reprogram the cells’ machinery to secrete high levels of the target protein at the injection site.
  • Some viral vector-based approaches have showed successful gene transfer with persistent therapeutic levels of transgene expression in the equine joint. This success indicates that gene therapy could be a promising approach for OA treatment.

The Role of Horses in Osteoarthritis Research

  • Horses serve as an effective model for studying OA because they exhibit similar joint characteristics to humans, both anatomically and mechanically.
  • Like humans, horses experience naturally occurring OA and undergo similar therapies to human patients. This makes them a clinically relevant population for OA research.
  • Conducting further studies on horses could help advance the field of OA therapy. It could also improve treatment for equine patients with naturally occurring joint disease.

Summary of Article

  • The article reviews the advancements in gene therapeutic approaches for treating OA. It also discusses the role of horses both as a relevant patient population and as an effective species for a translational model.

Cite This Article

APA
Thampi P, Samulski RJ, Grieger JC, Phillips JN, McIlwraith CW, Goodrich LR. (2022). Gene therapy approaches for equine osteoarthritis. Front Vet Sci, 9, 962898. https://doi.org/10.3389/fvets.2022.962898

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 9
Pages: 962898

Researcher Affiliations

Thampi, Parvathy
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States.
Samulski, R Jude
  • Gene Therapy Center, University of North Carolina, Chapel Hill, NC, United States.
Grieger, Joshua C
  • Gene Therapy Center, University of North Carolina, Chapel Hill, NC, United States.
Phillips, Jennifer N
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States.
McIlwraith, C Wayne
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States.
Goodrich, Laurie R
  • Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, College of Veterinary Medicine, Colorado State University, Fort Collins, CO, United States.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

This article includes 213 references
  1. Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA. Insurer and out-of-Pocket costs of osteoarthritis in the us: evidence from national survey data. Arthritis Rheum (2009) 60:3546–53.
    doi: 10.1002/art.24984pubmed: 19950287google scholar: lookup
  2. Cisternas MG, Murphy L, Sacks JJ, Solomon DH, Pasta DJ, Helmick CG. Alternative methods for defining osteoarthritis and the impact on estimating prevalence in a us population-based survey. Arthritis Care Res (2016) 68:574–80.
    doi: 10.1002/acr.22721pmc: PMC4769961pubmed: 26315529google scholar: lookup
  3. Dyson SJ, Ross MW. Diagnosis and Management of Lameness in the Horse. Philadelphia, PA: WB Saunders Company; (2011).
  4. Goodrich LR, Nixon AJ. Medical treatment of osteoarthritis in the horse - a review. Vet J (2006) 171:51–69.
    doi: 10.1016/j.tvjl.2004.07.008pubmed: 16427582google scholar: lookup
  5. McIlwraith CW, Frisbie DD, Kawcak CE. The horse as a model of naturally occurring osteoarthritis. Bone Joint Res (2012) 1:297–309.
    doi: 10.1302/2046-3758.111.2000132pmc: PMC3626203pubmed: 23610661google scholar: lookup
  6. USDA L, Lameness V. Laminitis in US Horses. Fort Collins, CO: USDA; APHIS; VS, CEAH, National Animal Health Monitoring System; (2000).
  7. Schlueter AE, Orth MW. Equine osteoarthritis: a brief review of the disease and its causes. Equine Comp Exerc Physiol (2004) 1:221–31.
    doi: 10.1079/ECP200428google scholar: lookup
  8. Keegan KG. Evidence-Based lameness detection and quantification. Vet Clin N Am Equine Prac (2007) 23:403–23.
    doi: 10.1016/j.cveq.2007.04.008pubmed: 17616320google scholar: lookup
  9. McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM. Oarsi guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage (2014) 22:363–88.
    doi: 10.1016/j.joca.2014.01.003pubmed: 24462672google scholar: lookup
  10. Gobbi A, Karnatzikos G, Kumar A. Long-Term results after microfracture treatment for full-thickness knee chondral lesions in athletes. Knee Surg Sports Traumatol Arthrosc (2014) 22:1986–96.
    doi: 10.1007/s00167-013-2676-8pubmed: 24051505google scholar: lookup
  11. Hangody L, Kish G, Kárpáti Z, Udvarhelyi I, Szigeti I, Bély M. Mosaicplasty for the Treatment of Articular Cartilage Defects: Application in Clinical Practice. Thorofare, NJ: SLACK Incorporated; (1998).
    doi: 10.3928/0147-7447-19980701-04pubmed: 9672912google scholar: lookup
  12. Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: surgical technique and rehabilitation to treat chondral defects. Clin Orthop Relat Res (2001) 391:S362–9.
    doi: 10.1097/00003086-200110001-00033pubmed: 11603719google scholar: lookup
  13. Torrie AM, Kesler WW, Elkin J, Gallo RA. Osteochondral allograft. Curr Rev Musculoskelet Med (2015) 8:413–22.
    doi: 10.1007/s12178-015-9298-3pmc: PMC4630219pubmed: 26475149google scholar: lookup
  14. Camargo Garbin L, Morris MJ. A comparative review of autologous conditioned serum and autologous protein solution for treatment of osteoarthritis in horses. Front Vet Sci (2021) 8:602978.
    doi: 10.3389/fvets.2021.602978pmc: PMC7933025pubmed: 33681323google scholar: lookup
  15. Garbin LC, Olver CS. Platelet-Rich products and their application to osteoarthritis. J Equine Vet Sci (2020) 86:102820.
    doi: 10.1016/j.jevs.2019.102820pubmed: 32067662google scholar: lookup
  16. Khurana A, Goyal A, Kirubakaran P, Akhand G, Gupta R, Goel N. Efficacy of autologous conditioned serum (Acs), platelet-rich plasma (Prp), hyaluronic acid (Ha) and steroid for early osteoarthritis knee: a comparative analysis. Indian J Orthop (2021) 55 (Suppl. 1):217–27.
    doi: 10.1007/s43465-020-00274-5pmc: PMC8149550pubmed: 34122773google scholar: lookup
  17. Le ADK, Enweze L, DeBaun MR, Dragoo JL. Platelet-Rich plasma. Clin Sports Med (2019) 38:17–44.
    doi: 10.1016/j.csm.2018.08.001pubmed: 30466721google scholar: lookup
  18. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med (1994) 331:889–95.
    doi: 10.1056/NEJM199410063311401pubmed: 8078550google scholar: lookup
  19. Brittberg M, Recker D, Ilgenfritz J, Saris DB, Group SES. Matrix-Applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med (2018) 46:1343–51.
    doi: 10.1177/0363546518756976pubmed: 29565642google scholar: lookup
  20. Devitt BM, Bell SW, Webster KE, Feller JA, Whitehead TS. Surgical treatments of cartilage defects of the knee: systematic review of randomised controlled trials. Knee (2017) 24:508–17.
    doi: 10.1016/j.knee.2016.12.002pubmed: 28189406google scholar: lookup
  21. Goyal D, Goyal A, Keyhani S, Lee EH, Hui JH. Evidence-Based status of second-and third-generation autologous chondrocyte implantation over first generation: a systematic review of level I and II studies. Arthroscopy (2013) 29:1872–8.
    doi: 10.1016/j.arthro.2013.07.271pubmed: 24075851google scholar: lookup
  22. Jacobi M, Villa V, Magnussen RA, Neyret P. Maci-a new era?. Sports Med Arthrosc Rehabil Ther Technol (2011) 3:1–7.
    doi: 10.1186/1758-2555-3-10pmc: PMC3117745pubmed: 21599919google scholar: lookup
  23. Baek S-H, Kim S-Y. Pharmacologic treatment of osteoarthritis. J Korean Med Assoc (2013) 56:1123–31.
    doi: 10.5124/jkma.2013.56.12.1123google scholar: lookup
  24. Kuyinu EL, Narayanan G, Nair LS, Laurencin CT. Animal models of osteoarthritis: classification, update, and measurement of outcomes. J Orthop Surg Res (2016) 11:19.
    doi: 10.1186/s13018-016-0346-5pmc: PMC4738796pubmed: 26837951google scholar: lookup
  25. Teeple E, Jay GD, Elsaid KA, Fleming BC. Animal models of osteoarthritis: challenges of model selection and analysis. AAPS J (2013) 15:438–46.
    doi: 10.1208/s12248-013-9454-xpmc: PMC3675748pubmed: 23329424google scholar: lookup
  26. Ahern BJ, Parvizi J, Boston R, Schaer TP. Preclinical animal models in single site cartilage defect testing: a systematic review. Osteoarthritis Cartilage (2009) 17:705–13.
    doi: 10.1016/j.joca.2008.11.008pubmed: 19101179google scholar: lookup
  27. Breinan HA, Minas T, Hsu H-P, Nehrer S, Shortkroff S, Spector M. Autologous chondrocyte implantation in a canine model: change in composition of reparative tissue with time. J Orthop Res (2001) 19:482–92.
    doi: 10.1016/S0736-0266(00)90015-9pubmed: 11398864google scholar: lookup
  28. Hurtig MB, Buschmann MD, Fortier LA, Hoemann CD, Hunziker EB, Jurvelin JS. Preclinical studies for cartilage repair: recommendations from the international cartilage repair society. Cartilage (2011) 2:137–52.
    doi: 10.1177/1947603511401905pmc: PMC4300779pubmed: 26069576google scholar: lookup
  29. Stricker-Krongrad A, Shoemake CR, Bouchard GF. The miniature swine as a model in experimental and translational medicine. Toxicol Pathol (2016) 44:612–23.
    doi: 10.1177/0192623316641784pubmed: 27073085google scholar: lookup
  30. Frisbie DD, Cross MW, McIlwraith CW. A comparative study of articular cartilage thickness in the stifle of animal species used in human pre-clinical studies compared to articular cartilage thickness in the human knee. Vet Comp Orthop Traumatol (2006) 19:142–6.
    doi: 10.1055/s-0038-1632990pubmed: 16971996google scholar: lookup
  31. Hembry RM, Dyce J, Driesang I, Hunziker EB, Fosang AJ, Tyler JA. Immunolocalization of matrix metalloproteinases in partial-thickness defects in pig articular cartilage. A preliminary report. J Bone Joint Surg Am (2001) 83:826–38.
    doi: 10.2106/00004623-200106000-00003pubmed: 11407790google scholar: lookup
  32. Malda J, Benders KE, Klein TJ, de Grauw JC, Kik MJ, Hutmacher DW. Comparative study of depth-dependent characteristics of equine and human osteochondral tissue from the medial and lateral femoral condyles. Osteoarthritis Cartilage (2012) 20:1147–51.
    doi: 10.1016/j.joca.2012.06.005pubmed: 22781206google scholar: lookup
  33. McIlwraith CW. From arthroscopy to gene therapy-−30 years of looking in joints. In: Proceedings of the Annual Convention Seattle, WA: (2005).
  34. Nelson BB, Goodrich LR, Barrett MF, Grinstaff MW, Kawcak CE. Use of contrast media in computed tomography and magnetic resonance imaging in horses: techniques, adverse events and opportunities. Equine Vet J (2017) 49:410–24.
    doi: 10.1111/evj.12689pubmed: 28407291google scholar: lookup
  35. Nelson BB, Kawcak CE, Barrett MF, McIlwraith CW, Grinstaff MW, Goodrich LR. Recent advances in articular cartilage evaluation using computed tomography and magnetic resonance imaging. Equine Vet J (2018) 50:564–79.
    doi: 10.1111/evj.12808pubmed: 29344988google scholar: lookup
  36. Frisbie DD, Ghivizzani SC, Robbins PD, Evans CH, McIlwraith CW. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther (2002) 9:12–20.
    doi: 10.1038/sj.gt.3301608pubmed: 11850718google scholar: lookup
  37. Wilke MM, Nydam DV, Nixon AJ. Enhanced early chondrogenesis in articular defects following arthroscopic mesenchymal stem cell implantation in an equine model. J Orthop Res (2007) 25:913–25.
    doi: 10.1002/jor.20382pubmed: 17405160google scholar: lookup
  38. Estrada McDermott J, Pezzanite L, Goodrich L, Santangelo K, Chow L, Dow S. Role of innate immunity in initiation and progression of osteoarthritis, with emphasis on horses. Animals (2021) 11:3247.
    doi: 10.3390/ani11113247pmc: PMC8614551pubmed: 34827979google scholar: lookup
  39. Frisbie DD. Synovial joint biology and pathobiology. In: Auer JA, Stick JA. editors. Equine Surgery. 4th ed. Saint Louis, MO: W.B. Saunders Company; (2012). p. 1096–114.
  40. McIlwraith CW. Traumatic arthritis and posttraumatic osteoarthritis in the horse. In Mcllwraith CW, Frisbie DD, Kawcak CE, van Weeran PR. editors. Joint Disease in the Horse. 2nd ed. Edinburgh: W. B. Saunders Company; (2016). p. 33–48.
  41. Wu CL, Harasymowicz NS, Klimak MA, Collins KH, Guilak F. the role of macrophages in osteoarthritis and cartilage repair. Osteoarthritis Cartilage (2020) 28:544–54.
    doi: 10.1016/j.joca.2019.12.007pmc: PMC7214213pubmed: 31926267google scholar: lookup
  42. Woodell-May JE, Sommerfeld SD. Role of inflammation and the immune system in the progression of osteoarthritis. J Orthop Res (2020) 38:253–7.
    doi: 10.1002/jor.24457pubmed: 31469192google scholar: lookup
  43. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM. Low-Grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol (2016) 12:580–92.
    doi: 10.1038/nrrheum.2016.136pmc: PMC5500215pubmed: 27539668google scholar: lookup
  44. Scanzello CR. Role of low-grade inflammation in osteoarthritis. Curr Opin Rheumatol (2017) 29:79–85.
    doi: 10.1097/BOR.0000000000000353pmc: PMC5565735pubmed: 27755180google scholar: lookup
  45. Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis (2013) 5:77–94.
    doi: 10.1177/1759720X12467868pmc: PMC3638313pubmed: 23641259google scholar: lookup
  46. Choi MC, Jo J, Park J, Kang HK, Park Y. Nf-Kb signaling pathways in osteoarthritic cartilage destruction. Cells (2019) 8:734.
    doi: 10.3390/cells8070734pmc: PMC6678954pubmed: 31319599google scholar: lookup
  47. Tas SW, Vervoordeldonk MJ, Tak PP. Gene therapy targeting nuclear factor-kappab: towards clinical application in inflammatory diseases and cancer. Curr Gene Ther (2009) 9:160–70.
    doi: 10.2174/156652309788488569pmc: PMC2864453pubmed: 19519361google scholar: lookup
  48. Roman-Blas JA, Jimenez SA. Nf-Kb as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage (2006) 14:839–48.
    doi: 10.1016/j.joca.2006.04.008pubmed: 16730463google scholar: lookup
  49. Liu T, Zhang L, Joo D, Sun S-C. Nf-Kb signaling in inflammation. Signal Transduct Target Ther (2017) 2:17023.
    doi: 10.1038/sigtrans.2017.23pmc: PMC5661633pubmed: 29158945google scholar: lookup
  50. Evans CH, Kraus VB, Setton LA. Progress in intra-articular therapy. Nat Rev Rheumatol (2014) 10:11–22.
    doi: 10.1038/nrrheum.2013.159pmc: PMC4402210pubmed: 24189839google scholar: lookup
  51. Simkin PA. Synovial perfusion and synovial fluid solutes. Ann Rheum Dis (1995) 54:424–8.
    doi: 10.1136/ard.54.5.424pmc: PMC1005609pubmed: 7794054google scholar: lookup
  52. Larsen C, Ostergaard J, Larsen SW, Jensen H, Jacobsen S, Lindegaard C. Intra-Articular depot formulation principles: role in the management of postoperative pain and arthritic disorders. J Pharm Sci (2008) 97:4622–54.
    doi: 10.1002/jps.21346pubmed: 18306275google scholar: lookup
  53. Levings R, Smith A, Levings PP, Palmer GD, Dacanay A, Colahan P. Gene therapy for the treatment of equine osteoarthritis. In: Rutland C, Rizvanov A. editors. Equine Science. London: IntechOpen; (2020).
    doi: 10.5772/intechopen.93000google scholar: lookup
  54. Bandara G, Robbins PD, Georgescu HI, Mueller GM, Glorioso JC, Evans CH. Gene transfer to synoviocytes: prospects for gene treatment of arthritis. DNA Cell Biol (1992) 11:227–31.
    doi: 10.1089/dna.1992.11.227pubmed: 1567555google scholar: lookup
  55. Nixon AJ, Goodrich LR, Scimeca MS, Witte TH, Schnabel LV, Watts AE. Gene therapy in musculoskeletal repair. Ann N Y Acad Sci (2007) 1117:310–27.
    doi: 10.1196/annals.1402.065pubmed: 18056051google scholar: lookup
  56. Watson Levings RS, Broome TA, Smith AD, Rice BL, Gibbs EP, Myara DA. Gene therapy for osteoarthritis: pharmacokinetics of intra-articular self-complementary adeno-associated virus interleukin-1 receptor antagonist delivery in an equine model. Hum Gene Ther Clin Dev (2018) 29:90–100.
    doi: 10.1089/humc.2017.142pmc: PMC6007808pubmed: 29869540google scholar: lookup
  57. Kotani H, Newton PB III, Zhang S, Chiang YL, Otto E, Weaver L. Improved methods of retroviral vector transduction and production for gene therapy. Hum Gene Ther (1994) 5:19–28.
    doi: 10.1089/hum.1994.5.1-19pubmed: 8155767google scholar: lookup
  58. Mulligan RC. The basic science of gene therapy. Science (1993) 260:926–32.
    doi: 10.1126/science.8493530pubmed: 8493530google scholar: lookup
  59. Somia N, Verma IM. Gene therapy: trials and tribulations. Nat Rev Genet (2000) 1:91–9.
    doi: 10.1038/35038533pubmed: 11253666google scholar: lookup
  60. Evans CH. Gene therapies for osteoarthritis. Curr Rheumatol Rep (2004) 6:31–40.
    doi: 10.1007/s11926-004-0081-5pubmed: 14713400google scholar: lookup
  61. Kim SH, Lechman ER, Kim S, Nash J, Oligino TJ, Robbins PD. Ex vivo gene delivery of Il-1ra and soluble Tnf receptor confers a distal synergistic therapeutic effect in antigen-induced arthritis. Mol Ther (2002) 6:591–600.
    doi: 10.1006/mthe.2002.0711pubmed: 12409257google scholar: lookup
  62. Makarov SS, Olsen JC, Johnston WN, Anderle SK, Brown RR, Baldwin AS. Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist Cdna. Proc Natl Acad Sci USA (1996) 93:402–6.
    doi: 10.1073/pnas.93.1.402pmc: PMC40246pubmed: 8552648google scholar: lookup
  63. Armbruster N, Weber C, Wictorowicz T, Rethwilm A, Scheller C, Steinert AF. Ex vivo gene delivery to synovium using foamy viral vectors. J Gene Med (2014) 16:166–78.
    doi: 10.1002/jgm.2774pubmed: 25044583google scholar: lookup
  64. Gelse K, Jiang QJ, Aigner T, Ritter T, Wagner K, Pöschl E. Fibroblast-mediated delivery of growth factor complementary DNA into mouse joints induces chondrogenesis but avoids the disadvantages of direct viral gene transfer. Arthritis Rheum (2001) 44:1943–53.
    pubmed: 11508447doi: 10.1002/1529-0131(200108)44:8<1943::aid-art332>3.0.co;2-zgoogle scholar: lookup
  65. Day CS, Kasemkijwattana C, Menetrey J, Floyd SS Jr, Booth D, Moreland MS. Myoblast-Mediated gene transfer to the joint. J Orthop Res (1997) 15:894–903.
    doi: 10.1002/jor.1100150616pubmed: 9497816google scholar: lookup
  66. Bandara G, Mueller GM, Galea-Lauri J, Tindal MH, Georgescu HI, Suchanek MK. Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci USA (1993) 90:10764–8.
    doi: 10.1073/pnas.90.22.10764pmc: PMC47858pubmed: 8248169google scholar: lookup
  67. Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ. Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Joint Surg Br (2007) 89:672–85.
    doi: 10.1302/0301-620X.89B5.18343pubmed: 17540757google scholar: lookup
  68. Yokoo N, Saito T, Uesugi M, Kobayashi N, Xin KQ, Okuda K. Repair of articular cartilage defect by autologous transplantation of basic fibroblast growth factor gene-transduced chondrocytes with adeno-associated virus vector. Arthritis Rheum (2005) 52:164–70.
    doi: 10.1002/art.20739pubmed: 15641065google scholar: lookup
  69. Fortier LA, Mohammed HO, Lust G, Nixon AJ. Insulin-like growth factor-I enhances cell-based repair of articular cartilage. J Bone Joint Surg Br (2002) 84:276–88.
    doi: 10.1302/0301-620x.84b2.11167pubmed: 11922373google scholar: lookup
  70. Hidaka C, Goodrich LR, Chen CT, Warren RF, Crystal RG, Nixon AJ. Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res (2003) 21:573–83.
    doi: 10.1016/S0736-0266(02)00264-4pubmed: 12798054google scholar: lookup
  71. Ortved KF, Begum L, Mohammed HO, Nixon AJ. Implantation of Raav5-Igf-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. Mol Ther (2015) 23:363–73.
    doi: 10.1038/mt.2014.198pmc: PMC4445609pubmed: 25311491google scholar: lookup
  72. Ozeki N, Muneta T, Koga H, Nakagawa Y, Mizuno M, Tsuji K. Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. Osteoarthritis Cartilage (2016) 24:1061–70.
    doi: 10.1016/j.joca.2015.12.018pubmed: 26880531google scholar: lookup
  73. Horie M, Choi H, Lee RH, Reger RL, Ylostalo J, Muneta T. Intra-Articular injection of human mesenchymal stem cells (Mscs) promote rat meniscal regeneration by being activated to express indian hedgehog that enhances expression of type II collagen. Osteoarthritis Cartilage (2012) 20:1197–207.
    doi: 10.1016/j.joca.2012.06.002pmc: PMC3788634pubmed: 22750747google scholar: lookup
  74. Nita I, Ghivizzani S, Galea-Lauri J, Bandara G, Georgescu H, Robbins P. Direct gene delivery to synovium: an evaluation of potential vectors in vitro and in vivo. Arthritis Rheum (1996) 39:820–8.
    doi: 10.1002/art.1780390515pubmed: 8639179google scholar: lookup
  75. Roessler BJ, Allen ED, Wilson JM, Hartman JW, Davidson BL. Adenoviral-mediated gene transfer to rabbit synovium in vivo. J Clin Invest (1993) 92:1085–92.
    doi: 10.1172/JCI116614pmc: PMC294950pubmed: 8349791google scholar: lookup
  76. Ghivizzani SC, Lechman ER, Kang R, Tio C, Kolls J, Evans CH. Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor α soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci USA (1998) 95:4613–8.
    doi: 10.1073/pnas.95.8.4613pmc: PMC22538pubmed: 9539786google scholar: lookup
  77. Gouze E, Pawliuk R, Pilapil C, Gouze J-N, Fleet C, Palmer GD. In vivo gene delivery to synovium by lentiviral vectors. Mol Ther (2002) 5:397–404.
    doi: 10.1006/mthe.2002.0562pubmed: 11945066google scholar: lookup
  78. Adriaansen J, Tas SW, Klarenbeek PL, Bakker AC, Apparailly F, Firestein GS. Enhanced gene transfer to arthritic joints using adeno-associated virus type 5: implications for intra-articular gene therapy. Ann Rheum Dis (2005) 64:1677–84.
    doi: 10.1136/ard.2004.035063pmc: PMC1755308pubmed: 15878906google scholar: lookup
  79. Brower-Toland BD, Saxer RA, Goodrich LR, Mi Z, Robbins PD, Evans CH. Direct adenovirus-mediated insulin-like growth factor I gene transfer enhances transplant chondrocyte function. Hum Gene Ther (2001) 12:117–29.
    doi: 10.1089/104303401750061186pubmed: 11177549google scholar: lookup
  80. Goodrich LR, Brower-Toland BD, Warnick L, Robbins PD, Evans CH, Nixon AJ. Direct adenovirus-mediated Igf-I gene transduction of synovium induces persisting synovial fluid Igf-I ligand elevations. Gene Ther (2006) 13:1253–62.
    doi: 10.1038/sj.gt.3302757pubmed: 16708081google scholar: lookup
  81. Goodrich LR, Grieger JC, Phillips JN, Khan N, Gray SJ, McIlwraith CW. Scaavil-1ra dosing trial in a large animal model and validation of long-term expression with repeat administration for osteoarthritis therapy. Gene Ther (2015) 22:536–45.
    doi: 10.1038/gt.2015.21pmc: PMC5567794pubmed: 25902762google scholar: lookup
  82. Goodrich LR, Phillips JN, McIlwraith CW, Foti SB, Grieger JC, Gray SJ. 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) 2:e70.
    doi: 10.1038/mtna.2012.61pmc: PMC3586798pubmed: 23385523google scholar: lookup
  83. Hemphill D, McIlwraith C, Slayden R, Samulski R, Goodrich L. Adeno-Associated virus gene therapy vector scaavigf-I for transduction of equine articular chondrocytes and Rna-Seq analysis. Osteoarthritis Cartilage (2016) 24:902–11.
    doi: 10.1016/j.joca.2015.12.001pubmed: 26706703google scholar: lookup
  84. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P. Lmo2-Associated clonal t cell proliferation in two patients after gene therapy for scid-X1. Science (2003) 302:415–9.
    doi: 10.1126/science.1088547pubmed: 14564000google scholar: lookup
  85. Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab (2003) 80:148–58.
    doi: 10.1016/j.ymgme.2003.08.016pubmed: 14567964google scholar: lookup
  86. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P. Gene therapy of human severe combined immunodeficiency (Scid)-X1 disease. Science (2000) 288:669–72.
    doi: 10.1126/science.288.5466.669pubmed: 10784449google scholar: lookup
  87. Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E. A serious adverse event after successful gene therapy for x-linked severe combined immunodeficiency. N Engl J Med (2003) 348:255–6.
    doi: 10.1056/NEJM200301163480314pubmed: 12529469google scholar: lookup
  88. Gabner S, Ertl R, Velde K, Renner M, Jenner F, Egerbacher M. Cytokine-Induced interleukin-1 receptor antagonist protein expression in genetically engineered equine mesenchymal stem cells for osteoarthritis treatment. J Gene Med (2018) 20:e3021.
    doi: 10.1002/jgm.3021pmc: PMC6001542pubmed: 29608232google scholar: lookup
  89. Gouze E, Pawliuk R, Gouze J-N, Pilapil C, Fleet C, Palmer GD. Lentiviral-Mediated gene delivery to synovium: potent intra-articular expression with amplification by inflammation. Mol Ther (2003) 7:460–6.
    doi: 10.1016/S1525-0016(03)00024-8pubmed: 12727108google scholar: lookup
  90. Cameron AD, Even KM, Linardi RL, Berglund AK, Schnabel LV, Engiles JB. Adeno-Associated virus-mediated overexpression of interleukin-10 affects the immunomodulatory properties of equine bone marrow-derived mesenchymal stem cells. Hum Gene Ther (2021) 32:907–18.
    doi: 10.1089/hum.2020.319pubmed: 33843261google scholar: lookup
  91. Watson Levings RS, Smith AD, Broome TA, Rice BL, Gibbs EP, Myara DA. 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) 29:101–12.
    doi: 10.1089/humc.2017.143pmc: PMC6007806pubmed: 29869535google scholar: lookup
  92. Frisbie DD, McIlwraith CW. Gene therapy: future therapies in osteoarthritis. Vet Clin N Am Equine Prac (2001) 17:233–43.
    doi: 10.1016/S0749-0739(17)30059-7pubmed: 15658173google scholar: lookup
  93. Oligino T, Ghivizzani S, Wolfe D, Lechman E, Krisky D, Mi Z. Intra-Articular delivery of a herpes simplex virus Il-1ra gene vector reduces inflammation in a rabbit model of arthritis. Gene Ther (1999) 6:1713–20.
    doi: 10.1038/sj.gt.3301014pubmed: 10516720google scholar: lookup
  94. Glorioso JC, Krisky D, Marconi P, Oligino T, Ghivizzani SC, Robbins PD. Progress in development of herpes simplex virus gene vectors for treatment of rheumatoid arthritis. Adv Drug Deliv Rev (1997) 27:41–57.
    doi: 10.1016/S0169-409X(97)00021-5pubmed: 10837550google scholar: lookup
  95. Petersen GF, Hilbert B, Trope G, Kalle W, Strappe P. Efficient transduction of equine adipose-derived mesenchymal stem cells by Vsv-G pseudotyped lentiviral vectors. Res Vet Sci (2014) 97:616–22.
    doi: 10.1016/j.rvsc.2014.09.004pubmed: 25443656google scholar: lookup
  96. Chen S, Shiau A, Li Y, Lin Y, Lee C, Wu C. Suppression of collagen-induced arthritis by intra-articular lentiviral vector-mediated delivery of toll-like receptor 7 short hairpin Rna gene. Gene Ther (2012) 19:752–60.
    doi: 10.1038/gt.2011.173pubmed: 22089492google scholar: lookup
  97. Liu S, Kiyoi T, Takemasa E, Maeyama K. Intra-Articular lentivirus-mediated gene therapy targeting cracm1 for the treatment of collagen-induced arthritis. J Pharmacol Sci (2017) 133:130–8.
    doi: 10.1016/j.jphs.2017.02.001pubmed: 28258822google scholar: lookup
  98. Schaack J. Adenovirus vectors deleted for genes essential for viral DNA replication. Front Biosci (2005) 10:1146–55.
    doi: 10.2741/1607pubmed: 15769613google scholar: lookup
  99. Amalfitano A, Hauser MA, Hu H, Serra D, Begy CR, Chamberlain JS. Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted. J Virol (1998) 72:926–33.
    doi: 10.1128/JVI.72.2.926-933.1998pmc: PMC124562pubmed: 9444984google scholar: lookup
  100. Räty JK, Lesch HP, Wirth T, Ylä-Herttuala S. Improving safety of gene therapy. Curr Drug Saf (2008) 3:46–53.
    doi: 10.2174/157488608783333925pubmed: 18690980google scholar: lookup
  101. Wang H, Georgakopoulou A, Li C, Liu Z, Gil S, Bashyam A. Curative in vivo hematopoietic stem cell gene therapy of murine thalassemia using large regulatory elements. JCI Insight (2020) 5:e139538.
    doi: 10.1172/jci.insight.139538pmc: PMC7455141pubmed: 32814708google scholar: lookup
  102. Khoja S, Nitzahn M, Hermann K, Truong B, Borzone R, Willis B. Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy. Mol Genet Metab (2018) 124:243–53.
    doi: 10.1016/j.ymgme.2018.04.001pmc: PMC6076338pubmed: 29801986google scholar: lookup
  103. Brunetti-Pierri N, Ng P. 17—helper-dependent adenoviral vectors. In: Curiel DT. editor. Adenoviral Vectors for Gene Therapy. 2nd edition. San Diego, CA: Academic Press; (2016). p. 423–50.
    doi: 10.1016/B978-0-12-800276-6.00017-6google scholar: lookup
  104. Brunetti-Pierri N, Ng P. Helper-Dependent adenoviral vectors for liver-directed gene therapy. Hum Mol Genet (2011) 20:R7–13.
    doi: 10.1093/hmg/ddr143pmc: PMC3095052pubmed: 21470977google scholar: lookup
  105. Rosewell A, Vetrini F, Ng P. Helper-Dependent adenoviral vectors. J Genet Syndr Gene Ther (2011) Suppl 5:001.
    doi: 10.4172/2157-7412.S5-001pmc: PMC3923448pubmed: 24533227google scholar: lookup
  106. Brunetti-Pierri N, Ng P. Gene therapy with helper-dependent adenoviral vectors: lessons from studies in large animal models. Virus Genes (2017) 53:684–91.
    doi: 10.1007/s11262-017-1471-xpubmed: 28593513google scholar: lookup
  107. Brunetti-Pierri N, Nichols TC, McCorquodale S, Merricks E, Palmer DJ, Beaudet AL. Sustained phenotypic correction of canine hemophilia b after systemic administration of helper-dependent adenoviral vector. Hum Gene Ther (2005) 16:811–20.
    doi: 10.1089/hum.2005.16.811pubmed: 16000063google scholar: lookup
  108. Brown BD, Shi CX, Powell S, Hurlbut D, Graham FL, Lillicrap D. Helper-Dependent adenoviral vectors mediate therapeutic factor viii expression for several months with minimal accompanying toxicity in a canine model of severe hemophilia A. Blood (2004) 103:804–10.
    doi: 10.1182/blood-2003-05-1426pubmed: 14512318google scholar: lookup
  109. Mc CW, Seiler MP, Bertin TK, Ubhayakar K, Palmer DJ, Ng P. Helper-Dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia a model. J Thromb Haemost (2006) 4:1218–25.
    doi: 10.1111/j.1538-7836.2006.01901.xpmc: PMC3947717pubmed: 16706963google scholar: lookup
  110. Morral N, O'Neal W, Rice K, Leland M, Kaplan J, Piedra PA. Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons. Proc Natl Acad Sci USA (1999) 96:12816–21.
    doi: 10.1073/pnas.96.22.12816pmc: PMC23112pubmed: 10536005google scholar: lookup
  111. Brunetti-Pierri N, Ng T, Iannitti DA, Palmer DJ, Beaudet AL, Finegold MJ. Improved hepatic transduction, reduced systemic vector dissemination, and long-term transgene expression by delivering helper-dependent adenoviral vectors into the surgically isolated liver of nonhuman primates. Hum Gene Ther (2006) 17:391–404.
    doi: 10.1089/hum.2006.17.391pubmed: 16610927google scholar: lookup
  112. Unzu C, Melero I, Hervás-Stubbs S, Sampedro A, Mancheño U, Morales-Kastresana A. Helper-Dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression. Gene Therapy (2015) 22:856–65.
    doi: 10.1038/gt.2015.64pubmed: 26125605google scholar: lookup
  113. Brunetti-Pierri N, Ng T, Iannitti D, Cioffi W, Stapleton G, Law M. Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors. Hum Gene Ther (2013) 24:761–5.
    doi: 10.1089/hum.2013.071pmc: PMC3746245pubmed: 23902403google scholar: lookup
  114. Nixon AJ, Grol MW, Lang HM, Ruan MZC, Stone A, Begum L. Disease-Modifying osteoarthritis treatment with interleukin-1 receptor antagonist gene therapy in small and large animal models. Arthritis Rheumatol (2018) 70:1757–68.
    doi: 10.1002/art.40668pubmed: 30044894google scholar: lookup
  115. Ruan MZ, Cerullo V, Cela R, Clarke C, Lundgren-Akerlund E, Barry MA. Treatment of osteoarthritis using a helper-dependent adenoviral vector retargeted to chondrocytes. Mol Ther Methods Clin Dev (2016) 3:16008.
    doi: 10.1038/mtm.2016.8pmc: PMC5008224pubmed: 27626040google scholar: lookup
  116. Stone A, Grol MW, Ruan MZC, Dawson B, Chen Y, Jiang MM. Combinatorial Prg4 and Il-1ra gene therapy protects against hyperalgesia and cartilage degeneration in post-traumatic osteoarthritis. Hum Gene Ther (2019) 30:225–35.
    doi: 10.1089/hum.2018.106pmc: PMC6383580pubmed: 30070147google scholar: lookup
  117. Brunetti-Pierri N, Palmer DJ, Beaudet AL, Carey KD, Finegold M, Ng P. Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum Gene Ther (2004) 15:35–46.
    doi: 10.1089/10430340460732445pubmed: 14965376google scholar: lookup
  118. Samulski RJ, Muzyczka N. Aav-mediated gene therapy for research and therapeutic purposes. Annu Rev Virol (2014) 1:427–51.
    doi: 10.1146/annurev-virology-031413-085355pubmed: 26958729google scholar: lookup
  119. Meier AF, Fraefel C, Seyffert M. The interplay between adeno-associated virus and its helper viruses. Viruses (2020) 12:662.
    doi: 10.3390/v12060662pmc: PMC7354565pubmed: 32575422google scholar: lookup
  120. Weitzman MD, Fisher KJ, Wilson JM. Recruitment of wild-type and recombinant adeno-associated virus into adenovirus replication centers. J Virol (1996) 70:1845–54.
    doi: 10.1128/jvi.70.3.1845-1854.1996pmc: PMC190012pubmed: 8627709google scholar: lookup
  121. Martini S, Rocco P, Morales M. Adeno-Associated virus for cystic fibrosis gene therapy. Braz J Med Biol Res (2011) 44:1097–104.
    doi: 10.1590/S0100-879X2011007500123pubmed: 21952739google scholar: lookup
  122. Sun J, Hakobyan N, Valentino LA, Feldman BL, Samulski RJ, Monahan PE. Intraarticular factor Ix protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor Ix. Blood (2008) 112:4532–41.
    doi: 10.1182/blood-2008-01-131417pmc: PMC2954682pubmed: 18716130google scholar: lookup
  123. 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) 20:1697–702.
    doi: 10.1089/hum.2009.030pmc: PMC2861962pubmed: 19642864google scholar: lookup
  124. Pi Y, Zhang X, Shi J, Zhu J, Chen W, Zhang C. Targeted delivery of non-viral vectors to cartilage in vivo using a chondrocyte-homing peptide identified by phage display. Biomaterials (2011) 32:6324–32.
    doi: 10.1016/j.biomaterials.2011.05.017pubmed: 21624651google scholar: lookup
  125. Evans CH, Ghivizzani SC, Robbins PD. Gene delivery to joints by intra-articular injection. Hum Gene Ther (2018) 29:2–14.
    doi: 10.1089/hum.2017.181pmc: PMC5773261pubmed: 29160173google scholar: lookup
  126. Madry H, Cucchiarini M, Terwilliger EF, Trippel SB. Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum Gene Ther (2003) 14:393–402.
    doi: 10.1089/104303403321208998pubmed: 12659680google scholar: lookup
  127. Hemphill DD, McIlwraith CW, Samulski RJ, Goodrich LR. Adeno-Associated viral vectors show serotype specific transduction of equine joint tissue explants and cultured monolayers. Sci Rep (2014) 4:5861.
    doi: 10.1038/srep05861pmc: PMC4894424pubmed: 25069854google scholar: lookup
  128. Flotte TR, Afione SA, Conrad C, McGrath SA, Solow R, Oka H. Stable in vivo expression of the cystic fibrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc Natl Acad Sci USA (1993) 90:10613–7.
    doi: 10.1073/pnas.90.22.10613pmc: PMC47827pubmed: 7504271google scholar: lookup
  129. Guggino WB, Cebotaru L. Adeno-Associated virus (Aav) gene therapy for cystic fibrosis: current barriers and recent developments. Expert Opin Biol Ther (2017) 17:1265–73.
    doi: 10.1080/14712598.2017.1347630pmc: PMC5858933pubmed: 28657358google scholar: lookup
  130. Berns KI, Linden RM. The cryptic life style of adenoassociated virus. Bioessays (1995) 17:237–45.
    doi: 10.1002/bies.950170310pubmed: 7748178google scholar: lookup
  131. Salganik M, Hirsch ML, Samulski RJ. Adeno-associated virus as a mammalian DNA vector. Microbiol Spectr (2015) 3:10.1128/microbiolspec.MDNA3-0052-2014.
    doi: 10.1128/microbiolspec.MDNA3-0052-2014pmc: PMC4677393pubmed: 26350320google scholar: lookup
  132. Grieger JC, Samulski RJ. Adeno-Associated virus vectorology, manufacturing, and clinical applications. Methods Enzymol (2012) 507:229–54.
    doi: 10.1016/B978-0-12-386509-0.00012-0pubmed: 22365777google scholar: lookup
  133. McCarty DM, Fu H, Monahan PE, Toulson CE, Naik P, Samulski RJ. Adeno-Associated virus terminal repeat (Tr) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther (2003) 10:2112–8.
    doi: 10.1038/sj.gt.3302134pubmed: 14625565google scholar: lookup
  134. McCarty DM, Monahan PE, Samulski RJ. Self-Complementary recombinant adeno-associated virus (scaav) vectors promote efficient transduction independently of DNA synthesis. Gene Ther (2001) 8:1248–54.
    doi: 10.1038/sj.gt.3301514pubmed: 11509958google scholar: lookup
  135. McCarty DM. Self-Complementary aav vectors; advances and applications. Mol Ther (2008) 16:1648–56.
    doi: 10.1038/mt.2008.171pubmed: 18682697google scholar: lookup
  136. Kay JD, Gouze E, Oligino TJ, Gouze JN, Watson RS, Levings PP. Intra-Articular gene delivery and expression of interleukin-1ra mediated by self-complementary adeno-associated virus. J Gene Med (2009) 11:605–14.
    doi: 10.1002/jgm.1334pmc: PMC2876984pubmed: 19384892google scholar: lookup
  137. Natkunarajah M, Trittibach P, McIntosh J, Duran Y, Barker S, Smith A. Assessment of ocular transduction using single-stranded and self-complementary recombinant adeno-associated virus serotype 2/8. Gene Ther (2008) 15:463–7.
    doi: 10.1038/sj.gt.3303074pubmed: 18004402google scholar: lookup
  138. Zhao L, Huang J, Fan Y, Li J, You T, He S. Exploration of Crispr/Cas9-based gene editing as therapy for osteoarthritis. Ann Rheum Dis (2019) 78:676–82.
    doi: 10.1136/annrheumdis-2018-214724pmc: PMC6621547pubmed: 30842121google scholar: lookup
  139. Ramamoorth M, Narvekar A. Non viral vectors in gene therapy- an overview. J Clin Diagn Res (2015) 9:Ge01–6.
    doi: 10.7860/JCDR/2015/10443.5394pmc: PMC4347098pubmed: 25738007google scholar: lookup
  140. Uzieliene I, Kalvaityte U, Bernotiene E, Mobasheri A. Non-Viral gene therapy for osteoarthritis. Front Bioeng Biotechnol (2021) 8:618399.
    doi: 10.3389/fbioe.2020.618399pmc: PMC7838585pubmed: 33520968google scholar: lookup
  141. Clanchy FIL, Williams RO. Plasmid DNA as a safe gene delivery vehicle for treatment of chronic inflammatory disease. Exp Opin Biol Ther (2008) 8:1507–19.
    doi: 10.1517/14712598.8.10.1507pubmed: 18774919google scholar: lookup
  142. Hardee CL, Arévalo-Soliz LM, Hornstein BD, Zechiedrich L. Advances in non-viral DNA vectors for gene therapy. Genes (2017) 8:65.
    doi: 10.3390/genes8020065pmc: PMC5333054pubmed: 28208635google scholar: lookup
  143. Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-Viral vectors for gene-based therapy. Nat Rev Genet (2014) 15:541–55.
    doi: 10.1038/nrg3763pubmed: 25022906google scholar: lookup
  144. Watkins LR, Chavez RA, Landry R, Fry M, Green-Fulgham SM, Coulson JD. Targeted interleukin-10 plasmid DNA therapy in the treatment of osteoarthritis: toxicology and pain efficacy assessments. Brain Behav Immun (2020) 90:155–66.
    doi: 10.1016/j.bbi.2020.08.005pubmed: 32800926google scholar: lookup
  145. Ginn SL, Amaya AK, Alexander IE, Edelstein M, Abedi MR. Gene therapy clinical trials worldwide to 2017: an update. J Gene Med (2018) 20:e3015.
    doi: 10.1002/jgm.3015pubmed: 29575374google scholar: lookup
  146. van der Loo JCM, Wright JF. Progress and challenges in viral vector manufacturing. Hum Mol Genet (2015) 25:R42–52.
    doi: 10.1093/hmg/ddv451pmc: PMC4802372pubmed: 26519140google scholar: lookup
  147. Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol (2015) 11:234–42.
    doi: 10.1038/nrrheum.2015.28pmc: PMC4510987pubmed: 25776949google scholar: lookup
  148. Merten O-W, Schweizer M, Chahal P, Kamen AA. Manufacturing of viral vectors for gene therapy: part I. Upstream processing. Pharm Bioprocess (2014) 2:183–203.
    doi: 10.4155/pbp.14.16google scholar: lookup
  149. Merten OW. State-of-the-Art of the production of retroviral vectors. J Gene Med (2004) 6:S105–S24.
    doi: 10.1002/jgm.499pubmed: 14978755google scholar: lookup
  150. Emmerling VV, Pegel A, Milian EG, Venereo-Sanchez A, Kunz M, Wegele J. Rational plasmid design and bioprocess optimization to enhance recombinant adeno-associated virus (aav) productivity in mammalian Cells. Biotechnol J (2016) 11:290–7.
    doi: 10.1002/biot.201500176pubmed: 26284700google scholar: lookup
  151. Kutner RH, Puthli S, Marino MP, Reiser J. Simplified production and concentration of Hiv-1-based lentiviral vectors using hyperflask vessels and anion exchange membrane chromatography. BMC Biotechnol (2009) 9:61.
    doi: 10.1186/1472-6750-9-10pmc: PMC2649911pubmed: 19220915google scholar: lookup
  152. Lesch HP, Heikkilä KM, Lipponen EM, Valonen P, Müller A, Räsänen E. Process development of adenoviral vector production in fixed bed bioreactor: from bench to commercial scale. Hum Gene Ther (2015) 26:560–71.
    doi: 10.1089/hum.2015.081pubmed: 26176404google scholar: lookup
  153. Merten OW, Cruz P, Rochette C, Geny-Fiamma C, Bouquet C, Goncalves D. Comparison of different bioreactor systems for the production of high titer retroviral vectors. Biotechnol Prog (2001) 17:326–35.
    doi: 10.1021/bp000162zpubmed: 11312711google scholar: lookup
  154. Wang X, Olszewska M, Qu J, Wasielewska T, Bartido S, Hermetet G. Large-Scale clinical-grade retroviral vector production in a fixed-bed bioreactor. J Immunother (2015) 38:127.
    doi: 10.1097/CJI.0000000000000072pmc: PMC4353472pubmed: 25751502google scholar: lookup
  155. Galibert L, Merten O-W. Latest developments in the large-scale production of adeno-associated virus vectors in insect cells toward the treatment of neuromuscular diseases. J Invertebr Pathol (2011) 107:S80–93.
    doi: 10.1016/j.jip.2011.05.008pubmed: 21784234google scholar: lookup
  156. Lee J, Welsh M. Enhancement of calcium phosphate-mediated transfection by inclusion of adenovirus in coprecipitates. Gene Ther (1999) 6:676–82.
    doi: 10.1038/sj.gt.3300857pubmed: 10476228google scholar: lookup
  157. Pear WS, Nolan GP, Scott ML, Baltimore D. Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci USA (1993) 90:8392–6.
    doi: 10.1073/pnas.90.18.8392pmc: PMC47362pubmed: 7690960google scholar: lookup
  158. Segura MM, Mangion M, Gaillet B, Garnier A. New developments in lentiviral vector design, production and purification. Exp Opin Biol Ther (2013) 13:987–1011.
    doi: 10.1517/14712598.2013.779249pubmed: 23590247google scholar: lookup
  159. Xie Q, Bu W, Bhatia S, Hare J, Somasundaram T, Azzi A. The atomic structure of adeno-associated virus (Aav-2), a vector for human gene therapy. Proc Natl Acad Sci USA (2002) 99:10405–10.
    doi: 10.1073/pnas.162250899pmc: PMC124927pubmed: 12136130google scholar: lookup
  160. Elverum K, Whitman M. Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine. Gene Ther (2020) 27:537–44.
    doi: 10.1038/s41434-019-0074-7pmc: PMC7744278pubmed: 31024072google scholar: lookup
  161. Gee AP. Gmp car-T cell production. Best Pract Res Clin Haematol (2018) 31:126–34.
    doi: 10.1016/j.beha.2018.01.002pubmed: 29909913google scholar: lookup
  162. Iancu EM, Kandalaft LE. Challenges and advantages of cell therapy manufacturing under good manufacturing practices within the hospital setting. Curr Opin Biotechnol (2020) 65:233–41.
    doi: 10.1016/j.copbio.2020.05.005pubmed: 32663771google scholar: lookup
  163. Moutsatsou P, Ochs J, Schmitt RH, Hewitt CJ, Hanga MP. Automation in cell and gene therapy manufacturing: from past to future. Biotechnol Lett (2019) 41:1245–53.
    doi: 10.1007/s10529-019-02732-zpmc: PMC6811377pubmed: 31541330google scholar: lookup
  164. Heathman TR, Nienow AW, McCall MJ, Coopman K, Kara B, Hewitt CJ. The translation of cell-based therapies: clinical landscape and manufacturing challenges. Regen Med (2015) 10:49–64.
    doi: 10.2217/rme.14.73pubmed: 25562352google scholar: lookup
  165. Liu Y, Hourd P, Chandra A, Williams DJ. Human cell culture process capability: a comparison of manual and automated production. J Tissue Eng Regen Med (2010) 4:45–54.
    doi: 10.1002/term.217pubmed: 19842115google scholar: lookup
  166. Thomas RJ, Chandra A, Liu Y, Hourd PC, Conway PP, Williams DJ. Manufacture of a human mesenchymal stem cell population using an automated cell culture platform. Cytotechnology (2007) 55:31–9.
    doi: 10.1007/s10616-007-9091-2pmc: PMC2289788pubmed: 19002992google scholar: lookup
  167. Williams DJ, Thomas RJ, Hourd PC, Chandra A, Ratcliffe E, Liu Y. Precision manufacturing for clinical-quality regenerative medicines. Philos Trans R Soc A Math Phys Eng Sci (2012) 370:3924–49.
    doi: 10.1098/rsta.2011.0049pubmed: 22802496google scholar: lookup
  168. Mason C, Dunnill P. Assessing the value of autologous and allogeneic cells for regenerative medicine. Regener Med (2009) 4:835–53.
    doi: 10.2217/rme.09.64pubmed: 19903003google scholar: lookup
  169. Frisbie DD, Al-Sobayil F, Billinghurst RC, Kawcak CE, McIlwraith CW. Changes in synovial fluid and serum biomarkers with exercise and early osteoarthritis in horses. Osteoarthritis Cartilage (2008) 16:1196–204.
    doi: 10.1016/j.joca.2008.03.008pubmed: 18442931google scholar: lookup
  170. Izal I, Acosta CA, Ripalda P, Zaratiegui M, Ruiz J, Forriol F. Igf-1 gene therapy to protect articular cartilage in a rat model of joint damage. Arch Orthop Trauma Surg (2008) 128:239–47.
    doi: 10.1007/s00402-007-0407-7pubmed: 17661064google scholar: lookup
  171. Ishihara A, Bartlett JS, Bertone AL. Inflammation and immune response of intra-articular serotype 2 adeno-associated virus or adenovirus vectors in a large animal model. Arthritis (2012) 2012:735472.
    doi: 10.1155/2012/735472pmc: PMC3263587pubmed: 22288012google scholar: lookup
  172. Watson RS, Broome TA, Levings PP, Rice BL, Kay JD, Smith AD. Scaav-Mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints. Gene Ther (2013) 20:670–7.
    doi: 10.1038/gt.2012.81pmc: PMC3577988pubmed: 23151520google scholar: lookup
  173. Bruening W, Giasson B, Mushynski W, Durham HD. Activation of stress-activated map protein kinases up-regulates expression of transgenes driven by the cytomegalovirus immediate/early promoter. Nucleic Acids Res (1998) 26:486–9.
    doi: 10.1093/nar/26.2.486pmc: PMC147296pubmed: 9421504google scholar: lookup
  174. Svensson RU, Barnes JM, Rokhlin OW, Cohen MB, Henry MD. Chemotherapeutic agents up-regulate the cytomegalovirus promoter: implications for bioluminescence imaging of tumor response to therapy. Cancer Res (2007) 67:10445–54.
    doi: 10.1158/0008-5472.CAN-07-1955pubmed: 17974988google scholar: lookup
  175. Ramanathan M, Haskó G, Leibovich SJ. Analysis of signal transduction pathways in macrophages using expression vectors with cmv promoters: a cautionary tale. Inflammation (2005) 29:94–102.
    doi: 10.1007/s10753-006-9005-zpubmed: 16865543google scholar: lookup
  176. Jacques C, Gosset M, Berenbaum F, Gabay C. The role of Il-1 and Il-1ra in joint inflammation and cartilage degradation. Vitam Horm (2006) 74:371–403.
    doi: 10.1016/S0083-6729(06)74016-Xpubmed: 17027524google scholar: lookup
  177. Joosten LA, Helsen MM, Saxne T, van de Loo FA, Heinegård D, van den Berg WB. Il-1αβ blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas Tnf-α blockade only ameliorates joint inflammation. J Immunol (1999) 163:5049–55.
    pubmed: 10528210
  178. Hung G, Galea-Lauri J, Mueller G, Georgescu H, Larkin L, Suchanek M. Suppression of Intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Ther (1994) 1:64–9.
    pubmed: 7584062
  179. 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) 43:289–97.
    pubmed: 10693868doi: 10.1002/1529-0131(200002)43:2<289::aid-anr8>3.0.co;2-hgoogle scholar: lookup
  180. Geng Y, Blanco FJ, Cornelisson M, Lotz M. Regulation of cyclooxygenase-2 expression in normal human articular chondrocytes. J Immunol (1995) 155:796–801.
    pubmed: 7608556
  181. Stadler J, Stefanovic-Racic M, Billiar T, Curran R, McIntyre L, Georgescu H. Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide. J Immunol (1991) 147:3915–20.
    pubmed: 1658153
  182. Howard RD, McIlwraith CW, Trotter GW, Nyborg JK. Cloning of equine interleukin 1 receptor antagonist and determination of its full-length Cdna sequence. Am J Vet Res (1998) 59:712–6.
    pubmed: 9622739
  183. Chevalier X, Goupille P, Beaulieu AD, Burch FX, Bensen WG, Conrozier T. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Care Res (2009) 61:344–52.
    doi: 10.1002/art.24096pubmed: 19248129google scholar: lookup
  184. Cohen SB, Woolley JM, Chan W, Group AS. Interleukin 1 receptor antagonist anakinra improves functional status in patients with rheumatoid arthritis. J Rheumatol (2003) 30:225–31.
    pubmed: 12563672
  185. Kary S, Burmester G. Anakinra: the first interleukin-1 inhibitor in the treatment of rheumatoid arthritis. Int J Clin Pract (2003) 57:231–4.
    pubmed: 12723729
  186. Fleischmann R. Addressing the safety of anakinra in patients with rheumatoid arthritis. Rheumatology (2003) 42:ii29–35.
    doi: 10.1093/rheumatology/keg330pubmed: 12817093google scholar: lookup
  187. Nixon AJ, Haupt JL, Frisbie DD, Morisset SS, McIlwraith CW, Robbins PD. Gene-Mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy. Gene Ther (2005) 12:177–86.
    doi: 10.1038/sj.gt.3302396pubmed: 15578043google scholar: lookup
  188. Fortier LA, Nixon AJ, Lust G. Phenotypic expression of equine articular chondrocytes grown in three-dimensional cultures supplemented with supraphysiologic concentrations of insulin-like growth factor-I. J Am Vet Med Assoc (2002) 63:301–5.
    doi: 10.2460/ajvr.2002.63.301pubmed: 11843134google scholar: lookup
  189. Tyler JA. Insulin-Like growth factor 1 can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines. Biochem J (1989) 260:543–8.
    doi: 10.1042/bj2600543pmc: PMC1138702pubmed: 2788408google scholar: lookup
  190. Mi Z, Ghivizzani SC, Lechman ER, Jaffurs D, Glorioso JC, Evans CH. Adenovirus-Mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints. Arthritis Rheum (2000) 43:2563–70.
    pubmed: 11083281doi: 10.1002/1529-0131(200011)43:11<2563::aid-anr25>3.0.co;2-8google scholar: lookup
  191. Paul R, Haydon RC, Cheng H, Ishikawa A, Nenadovich N, Jiang W. Potential use of Sox9 gene therapy for intervertebral degenerative disc disease. Spine (2003) 28:755–63.
    doi: 10.1097/01.BRS.0000058946.64222.92pmc: PMC4123440pubmed: 12698117google scholar: lookup
  192. Ren S, Liu Y, Ma J, Liu Y, Diao Z, Yang D. Treatment of rabbit intervertebral disc degeneration with co-transfection by adeno-associated virus-mediated Sox9 and osteogenic protein-1 double genes in vivo. Int J Mol Med (2013) 32:1063–8.
    doi: 10.3892/ijmm.2013.1497pubmed: 24045878google scholar: lookup
  193. Daniels O, Frisch J, Venkatesan JK, Rey-Rico A, Schmitt G, Cucchiarini M. Effects of raav-mediated Sox9 overexpression on the biological activities of human osteoarthritic articular chondrocytes in their intrinsic three-dimensional environment. J Clin Med (2019) 8:1637.
    doi: 10.3390/jcm8101637pmc: PMC6832991pubmed: 31591319google scholar: lookup
  194. Tao K, Rey-Rico A, Frisch J, Venkatesan JK, Schmitt G, Madry H. Raav-Mediated combined gene transfer and overexpression of Tgf-β and sox9 remodels human osteoarthritic articular cartilage. J Orthop Res (2016) 34:2181–90.
    doi: 10.1002/jor.23228pubmed: 26970525google scholar: lookup
  195. Neumann E, Judex M, Kullmann F, Grifka J, Robbins PD, Pap T. Inhibition of cartilage destruction by double gene transfer of Il-1ra and Il-10 involves the activin pathway. Gene Therapy (2002) 9:1508–19.
    doi: 10.1038/sj.gt.3301811pubmed: 12407423google scholar: lookup
  196. Fellowes R, Etheridge CJ, Coade S, Cooper RG, Stewart L, Miller AD. Amelioration of Established collagen induced arthritis by systemic Il-10 gene delivery. Gene Ther (2000) 7:967–77.
    doi: 10.1038/sj.gt.3301165pubmed: 10849557google scholar: lookup
  197. Vermeij EA, Broeren MG, Bennink MB, Arntz OJ, Gjertsson I, van Lent PL. Disease-Regulated local Il-10 gene therapy diminishes synovitis and cartilage proteoglycan depletion in experimental arthritis. Ann Rheum Dis (2015) 74:2084–91.
    doi: 10.1136/annrheumdis-2014-205223pubmed: 25028707google scholar: lookup
  198. Ma Y, Thornton S, Duwel LE, Boivin GP, Giannini EH, Leiden JM. Inhibition of collagen-induced arthritis in mice by viral Il-10 gene transfer. J Immunol (1998) 161:1516–24.
    pubmed: 9686619
  199. Apparailly F, Verwaerde C, Jacquet C, Auriault C, Sany J, Jorgensen C. Adenovirus-mediated transfer of viral Il-10 gene inhibits murine collagen-induced arthritis. J Immunol (1998) 160:5213–20.
    pubmed: 9605116
  200. Whalen JD, Lechman EL, Carlos CA, Weiss K, Kovesdi I, Glorioso JC. Adenoviral transfer of the viral Il-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. J Immunol (1999) 162:3625–32.
    pubmed: 10092823
  201. Wieseler-Frank J, Maier SF, Watkins LR. Central proinflammatory cytokines and pain enhancement. Neurosignals (2005) 14:166–74.
    doi: 10.1159/000087655pubmed: 16215299google scholar: lookup
  202. Kwilasz AJ, Grace PM, Serbedzija P, Maier SF, Watkins LR. The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology (2015) 96(Pt A):55–69.
    doi: 10.1016/j.neuropharm.2014.10.020pmc: PMC5144739pubmed: 25446571google scholar: lookup
  203. Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain Behav Immunity (2007) 21:686–98.
    doi: 10.1016/j.bbi.2006.10.012pmc: PMC2063454pubmed: 17174526google scholar: lookup
  204. Ortved KF, Begum L, Stefanovski D, Nixon AJ. Aav-mediated overexpression of Il-10 mitigates the inflammatory cascade in stimulated equine chondrocyte pellets. Current Gene Therapy (2018) 18:171–9.
    doi: 10.2174/1566523218666180510165123pubmed: 29749312google scholar: lookup
  205. Moss KL, Jiang Z, Dodson ME, Linardi RL, Haughan J, Gale AL. Sustained Interleukin-10 transgene expression following intra-articular Aav5-Il-10 administration to horses. Hum Gene Ther (2020) 31:110–8.
    doi: 10.1089/hum.2019.195pmc: PMC7872004pubmed: 31773987google scholar: lookup
  206. Reesink HL, Watts AE, Mohammed HO, Jay GD, Nixon AJ. Lubricin/Proteoglycan 4 increases in both experimental and naturally occurring equine osteoarthritis. Osteoarthritis Cartilage (2017) 25:128–37.
    doi: 10.1016/j.joca.2016.07.021pmc: PMC5489058pubmed: 27498214google scholar: lookup
  207. Jay GD, Torres JR, Warman ML, Laderer MC, Breuer KS. The role of lubricin in the mechanical behavior of synovial fluid. Proc Natl Acad Sci USA (2007) 104:6194–9.
    doi: 10.1073/pnas.0608558104pmc: PMC1851076pubmed: 17404241google scholar: lookup
  208. Flannery CR, Zollner R, Corcoran C, Jones AR, Root A, Rivera-Bermúdez MA. Prevention of cartilage degeneration in a rat model of osteoarthritis by intraarticular treatment with recombinant lubricin. Arthritis Rheum (2009) 60:840–7.
    doi: 10.1002/art.24304pubmed: 19248108google scholar: lookup
  209. Chavez RD, Sohn P, Serra R. Prg4 prevents osteoarthritis induced by dominant-negative interference of Tgf-ß signaling in mice. PLoS ONE (2019) 14:e0210601.
    doi: 10.1371/journal.pone.0210601pmc: PMC6328116pubmed: 30629676google scholar: lookup
  210. Ruan MZC, Erez A, Guse K, Dawson B, Bertin T, Chen Y. Proteoglycan 4 expression protects against the development of osteoarthritis. Sci Transl Med (2013) 5:176ra34.
    doi: 10.1126/scitranslmed.3005409pmc: PMC3804124pubmed: 23486780google scholar: lookup
  211. Sellers RS, Zhang R, Glasson SS, Kim HD, Peluso D, D'Augusta DA. Repair of articular cartilage defects one year after treatment with recombinant human bone morphogenetic protein-2 (Rhbmp-2). J Bone Joint Surg Am (2000) 82:151–60.
    doi: 10.2106/00004623-200002000-00001pubmed: 10682724google scholar: lookup
  212. Louwerse RT, Heyligers IC, Klein-Nulend J, Sugihara S, van Kampen GP, Semeins CM. Use of recombinant human osteogenic protein-1 for the repair of subchondral defects in articular cartilage in goats. J Biomed Mater Res (2000) 49:506–16.
    pubmed: 10602084doi: 10.1002/(sici)1097-4636(20000315)49:4<506::aid-jbm9>3.0.co;2-agoogle scholar: lookup
  213. Hidaka C, Quitoriano M, Warren RF, Crystal RG. Enhanced matrix synthesis and in vitro formation of cartilage-like tissue by genetically modified chondrocytes expressing Bmp-7. J Orthop Res (2001) 19:751–8.
    doi: 10.1016/S0736-0266(01)00019-5pubmed: 11562118google scholar: lookup

Citations

This article has been cited 4 times.
  1. Shi L, Khan MZ, Ullah A, Liang H, Geng M, Akhtar MF, Na J, Han Y, Wang C. Advancements in Stem Cell Applications for Livestock Research: A Review. Vet Sci 2025 Apr 23;12(5).
    doi: 10.3390/vetsci12050397pubmed: 40431490google scholar: lookup
  2. Kurhaluk N, Tkaczenko H. Recent Issues in the Development and Application of Targeted Therapies with Respect to Individual Animal Variability. Animals (Basel) 2025 Feb 6;15(3).
    doi: 10.3390/ani15030444pubmed: 39943214google scholar: lookup
  3. Puchalska M, Witkowska-Piłaszewicz O. Gene doping in horse racing and equine sports: Current landscape and future perspectives. Equine Vet J 2025 Mar;57(2):312-324.
    doi: 10.1111/evj.14418pubmed: 39267222google scholar: lookup
  4. Wilkin T, Hamilton NA, Cawley AT, Bhat S, Baoutina A. PCR-Based Equine Gene Doping Test for the Australian Horseracing Industry. Int J Mol Sci 2024 Feb 22;25(5).
    doi: 10.3390/ijms25052570pubmed: 38473816google scholar: lookup
Subscribe to our newsletter
Join 99,344 horse owners like you who receive our email updates on horse health and nutrition.