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Disease-Modifying Osteoarthritis Treatment With Interleukin-1 Receptor Antagonist Gene Therapy in Small and Large Animal Models.
Abstract: Gene therapy holds great promise for the treatment of osteoarthritis (OA) because a single intraarticular injection can lead to long-term expression of therapeutic proteins within the joint. This study was undertaken to investigate the use of a helper-dependent adenovirus (HDAd)-mediated intraarticular gene therapy approach for long-term expression of interleukin-1 receptor antagonist (IL-1Ra) as sustained symptomatic and disease-modifying therapy for OA. In mouse models of OA, efficacy of HDAd-IL-1Ra was evaluated by histologic analysis, micro-computed tomography (micro-CT), and hot plate analysis. In a horse OA model, safety and efficacy of HDAd-IL-1Ra were evaluated by blood chemistry, analyses of synovial fluid, synovial membrane, and cartilage, and gross pathology and lameness assessments. In skeletally immature mice, HDAd-IL-1Ra prevented development of cartilage damage, osteophytes, and synovitis. In skeletally immature and mature mice, treatment with HDAd-interleukin-1 receptor antagonist post-OA induction resulted in improved-albeit not significantly-cartilage status assessed histologically and significantly increased cartilage volume, cartilage surface, and bone surface covered by cartilage as assessed by micro-CT. Fewer osteophytes were observed in HDAd-IL-1Ra-treated skeletally immature mice. Synovitis was not affected in skeletally immature or mature mice. HDAd-IL-1Ra protected against disease-induced thermal hyperalgesia in skeletally mature mice. In the horse OA model, HDAd-IL-1Ra therapy significantly improved lameness parameters, indicating efficient symptomatic treatment. Moreover, macroscopically and histologically assessed cartilage and synovial membrane parameters were significantly improved, suggesting disease-modifying efficacy. These data from OA models in small and large animals demonstrated safe symptomatic and disease-modifying treatment with an HDAd-expressing IL-1Ra. Furthermore, this study establishes HDAd as a vector for joint gene therapy.
© 2018, American College of Rheumatology.
Publication Date: 2018-09-10 PubMed ID: 30044894DOI: 10.1002/art.40668Google 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.
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research article investigates the effectiveness of gene therapy, specifically Interleukin-1 Receptor Antagonist (IL-1Ra), in treating osteoarthritis (OA) in both small and large animal models. The study found evidence of the efficiency and safety of the approach, offering potential symptomatic treatment and disease modification.
Method and Scope of Research
- The research uses a helper-dependent adenovirus (HDAd)-mediated gene therapy protocol for the long-term expression of Interleukin-1 Receptor Antagonist (IL-1Ra) in osteoarthritis (OA) treatment.
- Small (mouse) and large (horse) animal models of OA were used to investigate this.
- Focused on both prevention and post-OA induction treatment, the study specifically looked at the evolution in cartilage damage, osteophytes, synovitis and OA-induced thermal hyperalgesia as well as the impact on lameness in the horse models.
Results of Mouse Models
- The gene therapy prevented development of cartilage damage, osteophytes, and synovitis in skeletally immature mice.
- Post-OA induction treatment in both immature and mature mice resulted in improved cartilage status and significant increases in cartilage volume, surface, and bone surface covered by cartilage.
- Treatment reduced the number of osteophytes in immature mice.
- Synovitis, an inflammation of the joint lining, remained unaffected in both immature and mature mice along with protecting against disease-induced thermal hyperalgesia or increased sensitivity to pain due to heat, in skeletally mature mice.
Results of Horse Models
- HDAd-IL-1Ra therapy significantly improved lameness parameters indicating effective symptomatic treatment.
- Improvements in cartilage and synovial membrane parameters were also highlighted, suggesting disease-modifying efficacy.
Overall Conclusion
- The study demonstrates the safe symptomatic treatment and disease-modifying capabilities of an HDAd vector expressing IL-1Ra in osteoarthritis models.
- These findings may pave the way for further development in joint gene therapies not just for osteoarthritis but potentially other degenerative joint diseases as well.
Cite This Article
APA
Nixon AJ, Grol MW, Lang HM, Ruan MZC, Stone A, Begum L, Chen Y, Dawson B, Gannon F, Plutizki S, Lee BHL, Guse K.
(2018).
Disease-Modifying Osteoarthritis Treatment With Interleukin-1 Receptor Antagonist Gene Therapy in Small and Large Animal Models.
Arthritis Rheumatol, 70(11), 1757-1768.
https://doi.org/10.1002/art.40668 Publication
Researcher Affiliations
- Cornell University, Ithaca, New York.
- Baylor College of Medicine, Houston, Texas.
- Cornell University, Ithaca, New York.
- Baylor College of Medicine, Houston, Texas.
- Baylor College of Medicine, Houston, Texas.
- Cornell University, Ithaca, New York.
- Baylor College of Medicine, Houston, Texas.
- Baylor College of Medicine, Houston, Texas.
- Baylor College of Medicine, Houston, Texas.
- GeneQuine Biotherapeutics GmbH, Hamburg, Germany.
- Baylor College of Medicine, Houston, Texas.
- Baylor College of Medicine, Houston, Texas, and GeneQuine Biotherapeutics GmbH, Hamburg, Germany.
MeSH Terms
- Adenoviridae
- Animals
- Arthritis, Experimental / therapy
- Carpal Joints / diagnostic imaging
- Carpal Joints / metabolism
- Carpal Joints / pathology
- Cartilage, Articular / diagnostic imaging
- Cartilage, Articular / metabolism
- Cartilage, Articular / pathology
- Disease Models, Animal
- Forelimb
- Genetic Therapy / methods
- Horses
- Interleukin 1 Receptor Antagonist Protein / genetics
- Interleukin 1 Receptor Antagonist Protein / metabolism
- Ligaments, Articular / surgery
- Mice
- Osteoarthritis / metabolism
- Osteoarthritis / therapy
- Osteophyte / diagnostic imaging
- Osteophyte / metabolism
- Osteophyte / pathology
- Stifle / diagnostic imaging
- Stifle / metabolism
- Stifle / pathology
- Synovial Fluid / metabolism
- Synovial Membrane / metabolism
- Synovitis / diagnostic imaging
- Synovitis / metabolism
- Synovitis / pathology
- X-Ray Microtomography
Grant Funding
- CIHR
Citations
This article has been cited 25 times.- Wolfe PN, Stoker AM, Crist BD, Leary E, Bozynski CC, Cook JL. Evaluation of mechanistic serum and urine biomarkers for secondary osteoarthritis associated with developmental dysplasia of the hip.. J Orthop 2023 Aug;42:24-29.
- Wilken F, Buschner P, Benignus C, Behr AM, Rieger J, Beckmann J. Pharmatherapeutic Treatment of Osteoarthrosis-Does the Pill against Already Exist? A Narrative Review.. J Pers Med 2023 Jun 30;13(7).
- Pezzanite LM, Timkovich AE, Sikes KJ, Chow L, Hendrickson DA, Becker JR, Webster A, Santangelo KS, Dow S. Erythrocyte removal from bone marrow aspirate concentrate improves efficacy as intra-articular cellular therapy in a rodent osteoarthritis model.. Ann Transl Med 2023 Jun 30;11(9):311.
- Floramo JS, Molchanov V, Liu H, Liu Y, Craig SEL, Yang T. An Integrated View of Stressors as Causative Agents in OA Pathogenesis.. Biomolecules 2023 Apr 22;13(5).
- Uebelhoer M, Lambert C, Grisart J, Guse K, Plutizki S, Henrotin Y. Interleukins, growth factors, and transcription factors are key targets for gene therapy in osteoarthritis: A scoping review.. Front Med (Lausanne) 2023;10:1148623.
- Khoramjouy M, Bayanati M, Noori S, Faizi M, Zarghi A. Effects of Ziziphus Jujuba Extract Alone and Combined with Boswellia Serrata Extract on Monosodium Iodoacetate Model of Osteoarthritis in Mice.. Iran J Pharm Res 2022 Dec;21(1):e134338.
- Evans CH, Ghivizzani SC, Robbins PD. Osteoarthritis gene therapy in 2022.. Curr Opin Rheumatol 2023 Jan 1;35(1):37-43.
- Liu Y, Liu C, Wang C, Zhang Q, Qu X, Liang C, Si C, Wang L. Treatment of Periodontal Inflammation in Diabetic Rats with IL-1ra Thermosensitive Hydrogel.. Int J Mol Sci 2022 Nov 11;23(22).
- Thampi P, Samulski RJ, Grieger JC, Phillips JN, McIlwraith CW, Goodrich LR. Gene therapy approaches for equine osteoarthritis.. Front Vet Sci 2022;9:962898.
- Cou015fkun HS, Yurtbay A, Say F. Platelet Rich Plasma Versus Autologous Conditioned Serum in Osteoarthritis of the Knee: Clinical Results of a Five-Year Retrospective Study.. Cureus 2022 Apr;14(4):e24500.
- Kumar N, Saraber P, Ding Z, Kusumbe AP. Diversity of Vascular Niches in Bones and Joints During Homeostasis, Ageing, and Diseases.. Front Immunol 2021;12:798211.
- Wang QS, Xu BX, Fan KJ, Fan YS, Teng H, Wang TY. Dexamethasone-loaded thermo-sensitive hydrogel attenuates osteoarthritis by protecting cartilage and providing effective pain relief.. Ann Transl Med 2021 Jul;9(14):1120.
- Grol MW, Haelterman NA, Lim J, Munivez EM, Archer M, Hudson DM, Tufa SF, Keene DR, Lei K, Park D, Kuzawa CD, Ambrose CG, Eyre DR, Lee BH. Tendon and motor phenotypes in the Crtap(-/-) mouse model of recessive osteogenesis imperfecta.. Elife 2021 May 26;10.
- Toyoda E, Maehara M, Watanabe M, Sato M. Candidates for Intra-Articular Administration Therapeutics and Therapies of Osteoarthritis.. Int J Mol Sci 2021 Mar 30;22(7).
- Weber AE, Bolia IK, Trasolini NA. Biological strategies for osteoarthritis: from early diagnosis to treatment.. Int Orthop 2021 Feb;45(2):335-344.
- Lamplot JD, Rai MF, Tompkins WP, Friedman MV, Schmidt EJ, Sandell LJ, Brophy RH. Gene Expression in Meniscal Tears at the Time of Arthroscopic Partial Meniscectomy Predicts the Progression of Osteoarthritis Within 6 Years of Surgery.. Orthop J Sports Med 2020 Aug;8(8):2325967120936275.
- Primorac D, Molnar V, Rod E, Jeleu010d u017d, u010cukelj F, Matiu0161iu0107 V, Vrdoljak T, Hudetz D, Hajsok H, Boriu0107 I. Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations.. Genes (Basel) 2020 Jul 26;11(8).
- Jayaram P, Liu C, Dawson B, Ketkar S, Patel SJ, Lee BH, Grol MW. Leukocyte-dependent effects of platelet-rich plasma on cartilage loss and thermal hyperalgesia in a mouse model of post-traumatic osteoarthritis.. Osteoarthritis Cartilage 2020 Oct;28(10):1385-1393.
- Vitali M, Ometti M, Drossinos A, Pironti P, Santoleri L, Salini V. Autologous conditioned serum: clinical and functional results using a novel disease modifying agent for the management of knee osteoarthritis.. J Drug Assess 2020;9(1):43-51.
- Salameh JW, Zhou L, Ward SM, Santa Chalarca CF, Emrick T, Figueiredo ML. Polymer-mediated gene therapy: Recent advances and merging of delivery techniques.. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2020 Mar;12(2):e1598.
- Moss KL, Jiang Z, Dodson ME, Linardi RL, Haughan J, Gale AL, Grzybowski C, Engiles JE, Stefanovski D, Robinson MA, Ortved KF. Sustained Interleukin-10 Transgene Expression Following Intra-Articular AAV5-IL-10 Administration to Horses.. Hum Gene Ther 2020 Jan;31(1-2):110-118.
- Cheng F, Yan FF, Liu YP, Cong Y, Sun KF, He XM. Dexmedetomidine inhibits the NF-u03baB pathway and NLRP3 inflammasome to attenuate papain-induced osteoarthritis in rats.. Pharm Biol 2019 Dec;57(1):649-659.
- Zhou Y, Ming J, Li Y, Deng M, Chen Q, Ma Y, Chen Z, Zhang Y, Liu S. Ligustilide attenuates nitric oxide-induced apoptosis in rat chondrocytes and cartilage degradation via inhibiting JNK and p38 MAPK pathways.. J Cell Mol Med 2019 May;23(5):3357-3368.
- Stone A, Grol MW, Ruan MZC, Dawson B, Chen Y, Jiang MM, Song IW, Jayaram P, Cela R, Gannon F, Lee BHL. Combinatorial Prg4 and Il-1ra Gene Therapy Protects Against Hyperalgesia and Cartilage Degeneration in Post-Traumatic Osteoarthritis.. Hum Gene Ther 2019 Feb;30(2):225-235.
- Evans C. Editorial: Arthritis Gene Therapy Using Interleukin-1 Receptor Antagonist.. Arthritis Rheumatol 2018 Nov;70(11):1699-1701.
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