Direct adenovirus-mediated IGF-I gene transduction of synovium induces persisting synovial fluid IGF-I ligand elevations.
Abstract: Insulin-like growth factor-I (IGF-I) is one of the most influential growth factors in cartilage repair. Maintenance of adequate IGF-I levels after articular repair procedures is complicated by the short biological half-life of IGF-I in vivo. This study investigated the potential for more prolonged IGF-I delivery through direct adenoviral mediated transduction of synovial tissues in the metacarpophalangeal (MCP) joints of horses. The use of a large animal model provided a structurally similar and metabolically relevant corollary to the human knee. The complete IGF-I coding sequence was packaged into an E1-E3 deleted adenovirus-5 vector under cytomegalovirus promoter control (AdIGF-I), and injected at varying total joint doses to the MCP joints of 14 horses. Direct injection of 20 and 50 x 10(10) AdIGF-I resulted in significant elevations of IGF-I in synovial fluid for approximately 21 days. Synovial tissue taken from injected joints at day 35 following injection and compared to tissue taken preinjection from the same joints revealed elevated synoviocyte IGF-I mRNA levels for the highest viral dose by in situ hybridization and real-time PCR techniques. AdIGF-I injections did not result in significant lameness, joint effusion or elevated total protein concentrations in the synovial fluid. Mild mononuclear infiltration of white blood cells was evident in histologic sections of the synovium in the second highest adenoviral IGF-I dose of 20 x 10(10) particles. Cartilage biopsies taken from all injected joints did not reveal any significant changes in proteoglycan levels nor in histological morphology, which included chondrocyte cloning, architecture, cell type or toluidine blue staining, when compared to control joints. Based on these findings, gene transfer of IGF-I to the synovium of joints can result in significant and persistent elevations of IGF-I ligand in synovial fluid with minimal detrimental effects. Direct IGF-I gene therapy may offer a simple approach in treating patients with acute cartilage injury.
Publication Date: 2006-05-18 PubMed ID: 16708081DOI: 10.1038/sj.gt.3302757Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The study explores the potential for longer-term delivery of Insulin-like growth factor-I (IGF-I), a key player in cartilage repair, via adenoviral mediated transduction of synovial tissues. Using horse MCP joints as a large animal model for human knees, it shows that injecting an adenovirus-5 vector with complete IGF-I coding sequence can significantly increase IGF-I levels in the synovial fluid for around 21 days, with minimal side effects.
Research Objective and Methodology
- The research aimed to explore a potential method for prolonged IGF-I delivery, a key factor in cartilage repair, considering its short biological half-life.
- The study was carried out by directly injecting an adenovirus-5 vector, which carries the complete IGF-I coding sequence (AdIGF-I), into the synovial tissues of MCP joints in horses. This acted as a structurally and metabolically relevant model for the human knee.
- Different total joint doses of AdIGF-I were injected into the MCP joints of 14 horses.
Results and Insights
- Direct injection of 20 and 50 x 10(10) AdIGF-I resulted in significant elevations of IGF-I in synovial fluid for roughly 21 days.
- Comparison of synovial tissue from injected joints at day 35 post-injection with tissue taken pre-injection revealed higher synoviocyte IGF-I mRNA levels for the highest viral dose.
- While no significant lameness, joint effusion or elevated total protein concentrations in the synovial fluid were found, a mild white blood cell infiltration was observed in histologic sections of the synovium with the second highest adenoviral IGF-I dose.
- Cartilage biopsies from all injected joints revealed no significant changes in proteoglycan levels or histological morphology.
Implications and Conclusion
- The findings show that gene transfer of IGF-I to the synovium of joints can initiate significant and lasting IGF-I ligand increases in synovial fluid with minimal harmful effects.
- Based on these results, direct IGF-I gene therapy could offer a novel approach in treating patients with acute cartilage damage, promising more extended period of cartilage repair benefits via IGF-I.
Cite This Article
APA
Goodrich LR, Brower-Toland BD, Warnick L, Robbins PD, Evans CH, Nixon AJ.
(2006).
Direct adenovirus-mediated IGF-I gene transduction of synovium induces persisting synovial fluid IGF-I ligand elevations.
Gene Ther, 13(17), 1253-1262.
https://doi.org/10.1038/sj.gt.3302757 Publication
Researcher Affiliations
- Comparative Orthopaedics Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
MeSH Terms
- Acute Disease
- Adenoviridae / genetics
- Animals
- Cartilage, Articular / injuries
- Cartilage, Articular / surgery
- Genetic Therapy / methods
- Genetic Vectors / administration & dosage
- Genetic Vectors / genetics
- Horses
- In Situ Hybridization / methods
- Injections, Intra-Articular
- Insulin-Like Growth Factor I / genetics
- Insulin-Like Growth Factor I / metabolism
- Ligands
- Metacarpophalangeal Joint
- Models, Animal
- RNA, Messenger / administration & dosage
- RNA, Messenger / analysis
- Reverse Transcriptase Polymerase Chain Reaction
- Synovial Fluid / metabolism
- Time Factors
- Transduction, Genetic / methods
- Treatment Outcome
- Wound Healing
Citations
This article has been cited 13 times.- Thampi P, Seabaugh KA, Pezzanite LM, Chu CR, Phillips JN, Grieger JC, McIlwraith CW, Samulski RJ, Goodrich LR. A pilot study to determine the optimal dose of scAAVIL-1ra in a large animal model of post-traumatic osteoarthritis. Gene Ther 2023 Sep 11;.
- Thampi P, Samulski RJ, Grieger JC, Phillips JN, McIlwraith CW, Goodrich LR. Gene therapy approaches for equine osteoarthritis. Front Vet Sci 2022;9:962898.
- Madry H, Venkatesan JK, Carballo-Pedrares N, Rey-Rico A, Cucchiarini M. Scaffold-Mediated Gene Delivery for Osteochondral Repair. Pharmaceutics 2020 Sep 29;12(10).
- Bellavia D, Veronesi F, Carina V, Costa V, Raimondi L, De Luca A, Alessandro R, Fini M, Giavaresi G. Gene therapy for chondral and osteochondral regeneration: is the future now?. Cell Mol Life Sci 2018 Feb;75(4):649-667.
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- 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 Jul 29;4:5861.
- 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.
- 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.
- Koch TG, Berg LC, Betts DH. Current and future regenerative medicine - principles, concepts, and therapeutic use of stem cell therapy and tissue engineering in equine medicine. Can Vet J 2009 Feb;50(2):155-65.
- Verwilghen DR, Vanderheyden L, Franck T, Busoni V, Enzerink E, Gangl M, Lejeune JP, van Galen G, Grulke S, Serteyn D. Variations of plasmatic concentrations of Insulin-like Growth Factor-I in post-pubescent horses affected with developmental osteochondral lesions. Vet Res Commun 2009 Oct;33(7):701-9.
- 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.
- Wang J, Su S, Dong C, Fan Q, Sun J, Liang S, Qin Z, Ma C, Jin J, Zhu H, Jiang T, Xu J. Human Adipose-derived Stem Cells Upregulate IGF-1 and Alleviate Osteoarthritis in a Two-stage Rabbit Osteoarthritis Model. Curr Stem Cell Res Ther 2024;19(11):1472-1483.
- Maihöfer J, Madry H, Rey-Rico A, Venkatesan JK, Goebel L, Schmitt G, Speicher-Mentges S, Cai X, Meng W, Zurakowski D, Menger MD, Laschke MW, Cucchiarini M. Hydrogel-Guided, rAAV-Mediated IGF-I Overexpression Enables Long-Term Cartilage Repair and Protection against Perifocal Osteoarthritis in a Large-Animal Full-Thickness Chondral Defect Model at One Year In Vivo. Adv Mater 2021 Apr;33(16):e2008451.
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