Login Register Cart 0
Generic placeholder image

Current Gene Therapy

Editor-in-Chief

ISSN (Print): 1566-5232
ISSN (Online): 1875-5631

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Single Injection AAV2-FGF18 Gene Therapy Reduces Cartilage Loss and Subchondral Bone Damage in a Mechanically Induced Model of Osteoarthritis

Author(s): Judith M. Hollander, Alex Goraltchouk, Jingshu Liu, Ellyn Xu, Francesco Luppino, Timothy E. McAlindon, Li Zeng* and Alexey Seregin*

Volume 24, Issue 4, 2024

Published on: 30 January, 2024

Page: [331 - 345] Pages: 15

DOI: 10.2174/0115665232275532231213063634

Price: $65

Abstract

Background: Osteoarthritis (OA) is a highly debilitating, degenerative pathology of cartilaginous joints affecting over 500 million people worldwide. The global economic burden of OA is estimated at $260-519 billion and growing, driven by aging global population and increasing rates of obesity. To date, only the multi-injection chondroanabolic treatment regimen of Fibroblast Growth Factor 18 (FGF18) has demonstrated clinically meaningful disease-modifying efficacy in placebo-controlled human trials. Our work focuses on the development of a novel single injection disease-modifying gene therapy, based on FGF18’s chondroanabolic activity.

Methods: OA was induced in Sprague-Dawley rats using destabilization of the medial meniscus (DMM) (3 weeks), followed by intra-articular treatment with 3 dose levels of AAV2-FGF18, rh- FGF18 protein, and PBS. Durability, redosability, and biodistribution were measured by quantifying nLuc reporter bioluminescence. Transcriptomic analysis was performed by RNA-seq on cultured human chondrocytes and rat knee joints. Morphological analysis was performed on knee joints stained with Safranin O/Fast Green and anti-PRG antibody.

Results: Dose-dependent reductions in cartilage defect size were observed in the AAV2-FGF18- treated joints relative to the vehicle control. Total defect width was reduced by up to 76% and cartilage thickness in the thinnest zone was increased by up to 106%. Morphologically, the vehicle- treated joints exhibited pronounced degeneration, ranging from severe cartilage erosion and bone void formation, to subchondral bone remodeling and near-complete subchondral bone collapse. In contrast, AAV2-FGF18-treated joints appeared more anatomically normal, with only regional glycosaminoglycan loss and marginal cartilage erosion. While effective at reducing cartilage lesions, treatment with rhFGF18 injections resulted in significant joint swelling (19% increase in diameter), as well as a decrease in PRG4 staining uniformity and intensity. In contrast to early-timepoint in vitro RNA-seq analysis, which showed a high degree of concordance between protein- and gene therapy-treated chondrocytes, in vivo transcriptomic analysis, revealed few gene expression changes following protein treatment. On the other hand, the gene therapy treatment exhibited a high degree of durability and localization over the study period, upregulating several chondroanabolic genes while downregulating OA- and fibrocartilage-associated markers.

Conclusion: FGF18 gene therapy treatment of OA joints can provide benefits to both cartilage and subchondral bone, with a high degree of localization and durability.

« Previous
Graphical Abstract

[1]
Leifer VP, Katz JN, Losina E. The burden of OA-health services and economics. Osteoarthritis Cartilage 2022; 30(1): 10-6.
[http://dx.doi.org/10.1016/j.joca.2021.05.007] [PMID: 34023527]
[2]
Singh JA, Tugwell P, Zanoli G, Wells GA. Total joint replacement surgery for knee osteoarthritis and other non-traumatic diseases: A network meta-analysis. Cochrane Libr 2019; 9.
[http://dx.doi.org/10.1002/14651858.CD011765.pub2]
[3]
Zhao X, Shah D, Gandhi K, et al. Clinical, humanistic, and economic burden of osteoarthritis among noninstitutionalized adults in the United States. Osteoarthritis Cartilage 2019; 27(11): 1618-26.
[http://dx.doi.org/10.1016/j.joca.2019.07.002] [PMID: 31299387]
[4]
Puig-Junoy J, Zamora A. Socio-economic costs of osteoarthritis: A systematic review of cost-of-illness studies. Semin Arthritis Rheum 2015; 44(5): 531-41.
[http://dx.doi.org/10.1016/j.semarthrit.2014.10.012] [PMID: 25511476]
[5]
U.S. Bureau of economic analysis. Table 1.1.5 gross domestic product. 2023. Available from: https://apps.bea.gov/iTable/?reqid=19&step=2&isuri=1&categories=survey#eyJhcHBpZCI6MTksInN0ZXBzIjpbMSwyLDNdLCJkYXRhIjpbWyJjYXRlZ29yaWVzIiwiU3VydmV5Il0sWyJOSVBBX1RhYmxlX0xpc3QiLCI1Il1dfQ== (Accessed July 28, 2023).
[6]
Long H, Liu Q, Yin H, et al. Prevalence trends of site-specific osteoarthritis from 1990 to 2019: Findings from the global burden of disease study 2019. Arthritis Rheumatol 2022; 74(7): 1172-83.
[http://dx.doi.org/10.1002/art.42089] [PMID: 35233975]
[7]
Abramoff B, Caldera FE. Osteoarthritis. Med Clin North Am 2020; 104(2): 293-311.
[http://dx.doi.org/10.1016/j.mcna.2019.10.007] [PMID: 32035570]
[8]
Cho Y, Jeong S, Kim H, et al. Disease-modifying therapeutic strategies in osteoarthritis: Current status and future directions. Exp Mol Med 2021; 53(11): 1689-96.
[http://dx.doi.org/10.1038/s12276-021-00710-y] [PMID: 34848838]
[9]
Taruc-Uy RL, Lynch SA. Diagnosis and treatment of osteoarthritis. Prim Care 2013; 40(4): 821-36.
[http://dx.doi.org/10.1016/j.pop.2013.08.003]
[10]
Crane NJ, Morris MD, Ignelzi MA, Yu G. Raman imaging demonstrates FGF2-induced craniosynostosis in mouse calvaria. J Biomed Opt 2005; 10(3): 031119.
[http://dx.doi.org/10.1117/1.1908057] [PMID: 16229644]
[11]
Im HJ, Li X, Muddasani P, et al. Basic fibroblast growth factor accelerates matrix degradation via a neuro-endocrine pathway in human adult articular chondrocytes. J Cell Physiol 2008; 215(2): 452-63.
[http://dx.doi.org/10.1002/jcp.21317] [PMID: 17960584]
[12]
Li X, Ellman MB, Kroin JS, et al. Species-specific biological effects of FGF-2 in articular cartilage: Implication for distinct roles within the FGF receptor family. J Cell Biochem 2012; 113(7): 2532-42.
[http://dx.doi.org/10.1002/jcb.24129] [PMID: 22415882]
[13]
Wang X, Manner PA, Horner A, Shum L, Tuan RS, Nuckolls GH. Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis Cartilage 2004; 12(12): 963-73.
[http://dx.doi.org/10.1016/j.joca.2004.08.008] [PMID: 15564063]
[14]
Yan D, Chen D, Im HJ. Fibroblast growth factor-2 promotes catabolism via FGFR1-Ras-Raf-MEK1/2-ERK1/2 axis that coordinates with the PKCδ pathway in human articular chondrocytes. J Cell Biochem 2012; 113(9): 2856-65.
[http://dx.doi.org/10.1002/jcb.24160] [PMID: 22488450]
[15]
Lattermann C, Luckett M. Staging and comorbidities. J Knee Surg 2011; 24(4): 217-24.
[http://dx.doi.org/10.1055/s-0031-1297362] [PMID: 22303751]
[16]
Bayer IS. Hyaluronic acid and controlled release: A review. Molecules 2020; 25(11): 2649.
[http://dx.doi.org/10.3390/molecules25112649] [PMID: 32517278]
[17]
Douglas RJ. Corticosteroid injection into the osteoarthritic knee: Drug selection, dose, and injection frequency. Int J Clin Pract 2012; 66(7): 699-704.
[http://dx.doi.org/10.1111/j.1742-1241.2012.02963.x] [PMID: 22698422]
[18]
Habib GS. Systemic effects of intra-articular corticosteroids. Clin Rheumatol 2009; 28(7): 749-56.
[http://dx.doi.org/10.1007/s10067-009-1135-x] [PMID: 19252817]
[19]
Eckstein F, Hochberg MC, Guehring H, et al. Long-term structural and symptomatic effects of intra-articular sprifermin in patients with knee osteoarthritis: 5-year results from the FORWARD study. Ann Rheum Dis 2021; 80(8): 1062-9.
[http://dx.doi.org/10.1136/annrheumdis-2020-219181] [PMID: 33962962]
[20]
Conaghan PG, Katz N, Hunter D, et al. POS1348 effects of sprifermin on a novel outcome of osteoarthritis symptom progression: post-hoc analysis of the forward randomized trial. Ann Rheum Dis 2023; 82 (1): 1025-6.
[http://dx.doi.org/10.1136/annrheumdis-2023-eular.2454]
[21]
Ohuchi H, Kimura S, Watamoto M, Itoh N. Involvement of fibroblast growth factor (FGF)18-FGF8 signaling in specification of left-right asymmetry and brain and limb development of the chick embryo. Mech Dev 2000; 95(1-2): 55-66.
[http://dx.doi.org/10.1016/S0925-4773(00)00331-2] [PMID: 10906450]
[22]
Whitsett JA, Clark JC, Picard L, et al. Fibroblast growth factor 18 influences proximal programming during lung morphogenesis. J Biol Chem 2002; 277(25): 22743-9.
[http://dx.doi.org/10.1074/jbc.M202253200] [PMID: 11927601]
[23]
Hu MCT, Qiu WR, Wang Y, et al. FGF-18, a novel member of the fibroblast growth factor family, stimulates hepatic and intestinal proliferation. Mol Cell Biol 1998; 18(10): 6063-74.
[http://dx.doi.org/10.1128/MCB.18.10.6063] [PMID: 9742123]
[24]
Kawano M, Komi-Kuramochi A, Asada M, et al. Comprehensive analysis of FGF and FGFR expression in skin: FGF18 is highly expressed in hair follicles and capable of inducing anagen from telogen stage hair follicles. J Invest Dermatol 2005; 124(5): 877-85.
[http://dx.doi.org/10.1111/j.0022-202X.2005.23693.x] [PMID: 15854025]
[25]
Chen G, An N, Shen J, et al. Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice. Nat Commun 2023; 14(1): 1235.
[http://dx.doi.org/10.1038/s41467-023-36895-1] [PMID: 36871047]
[26]
Lu S, Lin CW. Lentivirus-mediated transfer of gene encoding fibroblast growth factor-18 inhibits intervertebral disc degeneration. Exp Ther Med 2021; 22(2): 856.
[http://dx.doi.org/10.3892/etm.2021.10288] [PMID: 34178129]
[27]
Tong G, Chen X, Lee J, et al. Fibroblast growth factor 18 attenuates liver fibrosis and HSCs activation via the SMO-LATS1-YAP pathway. Pharmacol Res 2022; 178: 106139.
[http://dx.doi.org/10.1016/j.phrs.2022.106139] [PMID: 35202822]
[28]
Hollander JM, Goraltchouk A, Rawal M, et al. Adeno-associated virus-delivered fibroblast growth factor 18 gene therapy promotes cartilage anabolism. Cartilage 2023; 14(4): 492-505.
[http://dx.doi.org/10.1177/19476035231158774] [PMID: 36879540]
[29]
Glasson SS, Blanchet TJ, Morris EA. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 2007; 15(9): 1061-9.
[http://dx.doi.org/10.1016/j.joca.2007.03.006] [PMID: 17470400]
[30]
Gerwin N, Bendele AM, Glasson S, Carlson CS. The OARSI histopathology initiative – recommendations for histological assessments of osteoarthritis in the rat. Osteoarthritis Cartilage 2010; 18 (Suppl. 3): S24-34.
[http://dx.doi.org/10.1016/j.joca.2010.05.030] [PMID: 20864021]
[31]
Chang GH, Park LK, Le NA, et al. Subchondral bone length in knee osteoarthritis: A deep learning–derived imaging measure and its association with radiographic and clinical outcomes. Arthritis Rheumatol 2021; 73(12): 2240-8.
[http://dx.doi.org/10.1002/art.41808] [PMID: 33973737]
[32]
Adams EJ, Green JA, Clark AH, Youngson JH. Comparison of different scoring systems for immunohistochemical staining. J Clin Pathol 1999; 52(1): 75-7.
[http://dx.doi.org/10.1136/jcp.52.1.75] [PMID: 10343618]
[33]
Grevenstein D, Heilig J, Dargel J, et al. COMP in the infrapatellar fat pad—results of a prospective histological, immunohistological, and biochemical case–control study. J Orthop Res 2020; 38(4): 747-58.
[http://dx.doi.org/10.1002/jor.24514] [PMID: 31696983]
[34]
Babraham institute bioinformatics group. babraham bioinformatics - fastqc a quality control tool for high throughput sequence data. 2010. Available from: https://www.bioinformatics.babraham.ac.uk/projects/fastqc/ (Accessed June 9, 2023).
[35]
Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J 2011; 17(1): 10-2.
[http://dx.doi.org/10.14806/ej.17.1.200]
[36]
Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013; 29(1): 15-21.
[http://dx.doi.org/10.1093/bioinformatics/bts635] [PMID: 23104886]
[37]
Liao Y, Smyth GK, Shi W. featureCounts: An efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 2014; 30(7): 923-30.
[http://dx.doi.org/10.1093/bioinformatics/btt656] [PMID: 24227677]
[38]
Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15(12): 550.
[http://dx.doi.org/10.1186/s13059-014-0550-8] [PMID: 25516281]
[39]
Roemer FW, Neogi T, Nevitt MC, et al. Subchondral bone marrow lesions are highly associated with, and predict subchondral bone attrition longitudinally: The MOST study. Osteoarthritis Cartilage 2010; 18(1): 47-53.
[http://dx.doi.org/10.1016/j.joca.2009.08.018] [PMID: 19769930]
[40]
Coles JM, Zhang L, Blum JJ, et al. Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4. Arthritis Rheum 2010; 62(6): 1666-74.
[http://dx.doi.org/10.1002/art.27436] [PMID: 20191580]
[41]
Marcelino J, Carpten JD, Suwairi WM, et al. CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy- coxa vara-pericarditis syndrome. Nat Genet 1999; 23(3): 319-22.
[http://dx.doi.org/10.1038/15496] [PMID: 10545950]
[42]
Nugent-Derfus GE, Chan AH, Schumacher BL, Sah RL. PRG4 exchange between the articular cartilage surface and synovial fluid. J Orthop Res 2007; 25(10): 1269-76.
[http://dx.doi.org/10.1002/jor.20431] [PMID: 17546655]
[43]
Schumacher BL, Block JA, Schmid TM, Aydelotte MB, Kuettner KE. A novel proteoglycan synthesized and secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem Biophys 1994; 311(1): 144-52.
[http://dx.doi.org/10.1006/abbi.1994.1219] [PMID: 8185311]
[44]
Payne KA, Lee HH, Haleem AM, et al. Single intra-articular injection of adeno-associated virus results in stable and controllable in vivo transgene expression in normal rat knees. Osteoarthritis Cartilage 2011; 19(8): 1058-65.
[http://dx.doi.org/10.1016/j.joca.2011.04.009] [PMID: 21571082]
[45]
Shahmirzadi A, Edgar D, Liao CY, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab 2020; 32(3): 447-456.e6.
[http://dx.doi.org/10.1016/j.cmet.2020.08.004] [PMID: 32877690]
[46]
Phillips PM, Jarema KA, Kurtz DM, MacPhail RC. An observational assessment method for aging laboratory rats. J Am Assoc Lab Anim Sci 2010; 49(6): 792-9.
[PMID: 21205442]
[47]
Chen Q, Luo H, Zhou C, et al. Comparative intra-articular gene transfer of seven adeno-associated virus serotypes reveals that AAV2 mediates the most efficient transduction to mouse arthritic chondrocytes. PLoS One 2020; 15(12): e0243359.
[http://dx.doi.org/10.1371/journal.pone.0243359] [PMID: 33320893]
[48]
Yoon DS, Lee KM, Cho S, et al. Cellular and tissue selectivity of aav serotypes for gene delivery to chondrocytes and cartilage. Int J Med Sci 2021; 18(15): 3353-60.
[http://dx.doi.org/10.7150/ijms.56760] [PMID: 34522160]
[49]
Asanbaeva A, Masuda K, Thonar EJMA, Klisch SM, Sah RL. Cartilage growth and remodeling: Modulation of balance between proteoglycan and collagen network in vitro with β-aminopropionitrile. Osteoarthritis Cartilage 2008; 16(1): 1-11.
[http://dx.doi.org/10.1016/j.joca.2007.05.019] [PMID: 17631390]
[50]
Huang J, Zhao L, Chen D. Growth factor signalling in osteoarthritis. Growth Factors 2018; 36(5-6): 187-95.
[http://dx.doi.org/10.1080/08977194.2018.1548444] [PMID: 30624091]
[51]
Martin JA, Scherb MB, Lembke LA, Buckwalter JA. Damage control mechanisms in articular cartilage: The role of the insulin-like growth factor I axis. Iowa Orthop J 2000; 20: 1-10.
[PMID: 10934618]
[52]
Yunus MH, Lee Y, Nordin A, Chua KH, Idrus R. Remodeling osteoarthritic articular cartilage under hypoxic conditions. Int J Mol Sci 2022; 23(10): 5356.
[http://dx.doi.org/10.3390/ijms23105356] [PMID: 35628163]
[53]
Hu W, Chen Y, Dou C, Dong S. Microenvironment in subchondral bone: Predominant regulator for the treatment of osteoarthritis. Ann Rheum Dis 2021; 80(4): 413-22.
[http://dx.doi.org/10.1136/annrheumdis-2020-218089] [PMID: 33158879]
[54]
Hu Y, Chen X, Wang S, Jing Y, Su J. Subchondral bone microenvironment in osteoarthritis and pain. Bone Res 2021; 9(1): 20.
[http://dx.doi.org/10.1038/s41413-021-00147-z] [PMID: 33731688]
[55]
Li G, Yin J, Gao J, et al. Subchondral bone in osteoarthritis: Insight into risk factors and microstructural changes. Arthritis Res Ther 2013; 15(6): 223.
[http://dx.doi.org/10.1186/ar4405] [PMID: 24321104]
[56]
Zhu X, Chan YT, Yung PSH, Tuan RS, Jiang Y. Subchondral bone remodeling: A therapeutic target for osteoarthritis. Front Cell Dev Biol 2021; 8: 607764.
[http://dx.doi.org/10.3389/fcell.2020.607764] [PMID: 33553146]
[57]
Bay-Jensen AC, Manginelli AA, Karsdal M, et al. Low levels of type II collagen formation (PRO-C2) are associated with response to sprifermin: A pre-defined, exploratory biomarker analysis from the FORWARD study. Osteoarthritis Cartilage 2022; 30(1): 92-9.
[http://dx.doi.org/10.1016/j.joca.2021.10.008] [PMID: 34737064]
[58]
Siefen T, Bjerregaard S, Borglin C, Lamprecht A. Assessment of joint pharmacokinetics and consequences for the intraarticular delivery of biologics. J Control Release 2022; 348: 745-59.
[http://dx.doi.org/10.1016/j.jconrel.2022.06.015] [PMID: 35714731]
[59]
Gigout A, Guehring H, Froemel D, et al. Sprifermin (rhFGF18) enables proliferation of chondrocytes producing a hyaline cartilage matrix. Osteoarthritis Cartilage 2017; 25(11): 1858-67.
[http://dx.doi.org/10.1016/j.joca.2017.08.004] [PMID: 28823647]
[60]
Müller S, Lindemann S, Gigout A. Effects of Sprifermin, IGF1, IGF2, BMP7, or CNP on bovine chondrocytes in monolayer and 3D culture. J Orthop Res 2020; 38(3): 653-62.
[http://dx.doi.org/10.1002/jor.24491] [PMID: 31608492]
[61]
Sieber S, Gigout A. Sprifermin (recombinant human FGF18) is internalized through clathrin- and dynamin-independent pathways and degraded in primary chondrocytes. Exp Cell Res 2020; 395(2): 112236.
[http://dx.doi.org/10.1016/j.yexcr.2020.112236] [PMID: 32798495]
[62]
Chou CH, Lee MTM, Song IW, et al. Insights into osteoarthritis progression revealed by analyses of both knee tibiofemoral compartments. Osteoarthritis Cartilage 2015; 23(4): 571-80.
[http://dx.doi.org/10.1016/j.joca.2014.12.020] [PMID: 25575966]
[63]
Indjeian VB, Kingman GA, Jones FC, et al. Evolving new skeletal traits by cis -regulatory changes in bone morphogenetic proteins. Cell 2016; 164(1-2): 45-56.
[http://dx.doi.org/10.1016/j.cell.2015.12.007] [PMID: 26774823]
[64]
Settle SH Jr, Rountree RB, Sinha A, Thacker A, Higgins K, Kingsley DM. Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev Biol 2003; 254(1): 116-30.
[http://dx.doi.org/10.1016/S0012-1606(02)00022-2] [PMID: 12606286]
[65]
Alcaide-Ruggiero L, Molina-Hernández V, Granados MM, Domínguez JM. Main and minor types of collagens in the articular cartilage: The role of collagens in repair tissue evaluation in chondral defects. Int J Mol Sci 2021; 22(24): 13329.
[http://dx.doi.org/10.3390/ijms222413329] [PMID: 34948124]
[66]
Luo Y, Sinkeviciute D, He Y, et al. The minor collagens in articular cartilage. Protein Cell 2017; 8(8): 560-72.
[http://dx.doi.org/10.1007/s13238-017-0377-7] [PMID: 28213717]
[67]
Zelenski NA, Leddy HA, Sanchez-Adams J, et al. Type VI collagen regulates pericellular matrix properties, chondrocyte swelling, and mechanotransduction in mouse articular cartilage. Arthritis Rheumatol 2015; 67(5): 1286-94.
[http://dx.doi.org/10.1002/art.39034] [PMID: 25604429]
[68]
Benjamin M, Ralphs JR. Fibrocartilage in tendons and ligaments-an adaptation to compressive load. J Anat 1998; 193: 481-94.
[http://dx.doi.org/10.1046/j.1469-7580.1998.19340481.x]
[69]
Friedenberg SG, Zhu L, Zhang Z, et al. Evaluation of a fibrillin 2 gene haplotype associated with hip dysplasia and incipient osteoarthritis in dogs. Am J Vet Res 2011; 72(4): 530-40.
[http://dx.doi.org/10.2460/ajvr.72.4.530] [PMID: 21453155]
[70]
Lee JY, Lori D, Wells DJ, Kemp PR. FHL1 activates myostatin signalling in skeletal muscle and promotes atrophy. FEBS Open Bio 2015; 5(1): 753-62.
[http://dx.doi.org/10.1016/j.fob.2015.08.011] [PMID: 26504741]
[71]
S̆irca A, Sus̆ec-Michieli M. Selective type II fibre muscular atrophy in patients with osteoarthritis of the hip. J Neurol Sci 1980; 44(2-3): 149-59.
[http://dx.doi.org/10.1016/0022-510X(80)90123-9] [PMID: 6444440]
[72]
Karlsson M, Zhang C, Méar L, et al. A single–cell type transcriptomics map of human tissues. Sci Adv 2021; 7(31): eabh2169.
[http://dx.doi.org/10.1126/sciadv.abh2169] [PMID: 34321199]
[73]
Uhlen M, Karlsson MJ, Zhong W, et al. A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science 2019; 366(6472): eaax9198.
[http://dx.doi.org/10.1126/science.aax9198] [PMID: 31857451]
[74]
Loeser RF. Aging and osteoarthritis: The role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 2009; 17(8): 971-9.
[http://dx.doi.org/10.1016/j.joca.2009.03.002] [PMID: 19303469]
[75]
Lotz M, Loeser RF. Effects of aging on articular cartilage homeostasis. Bone 2012; 51(2): 241-8.
[http://dx.doi.org/10.1016/j.bone.2012.03.023] [PMID: 22487298]
[76]
Lee HH, O’Malley MJ, Friel NA, et al. Persistence, localization, and external control of transgene expression after single injection of adeno-associated virus into injured joints. Hum Gene Ther 2013; 24(4): 457-66.
[http://dx.doi.org/10.1089/hum.2012.118] [PMID: 23496155]
[77]
Levings RS, Broome TA, Smith AD, et al. 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(2): 90-100.
[http://dx.doi.org/10.1089/humc.2017.142] [PMID: 29869540]
[78]
Verdera HC, Kuranda K, Mingozzi F. AAV vector immunogenicity in humans: A long journey to successful gene transfer. Mol Ther 2020; 28(3): 723-46.
[http://dx.doi.org/10.1016/j.ymthe.2019.12.010] [PMID: 31972133]
[79]
Ail D, Ren D, Brazhnikova E, et al. Systemic and local immune responses to intraocular AAV vector administration in non-human primates. Mol Ther Methods Clin Dev 2022; 24: 306-16.
[http://dx.doi.org/10.1016/j.omtm.2022.01.011] [PMID: 35229004]
[80]
Leborgne C, Barbon E, Alexander JM, et al. IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies. Nat Med 2020; 26(7): 1096-101.
[http://dx.doi.org/10.1038/s41591-020-0911-7] [PMID: 32483358]
[81]
Kalbhen DA. Chemical model of osteoarthritis-a pharmacological evaluation. J Rheumatol 1987; 14(Spec No): 130-1.
[PMID: 3625668]
[82]
Takahashi I, Matsuzaki T, Kuroki H, Hoso M. Induction of osteoarthritis by injecting monosodium iodoacetate into the patellofemoral joint of an experimental rat model. PLoS One 2018; 13(4): e0196625.
[http://dx.doi.org/10.1371/journal.pone.0196625] [PMID: 29698461]
[83]
Moore EE, Bendele AM, Thompson DL, et al. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 2005; 13(7): 623-31.
[http://dx.doi.org/10.1016/j.joca.2005.03.003] [PMID: 15896984]
[84]
Hendesi H, Stewart S, Gibison ML, Guehring H, Richardson DW, Dodge GR. Recombinant fibroblast growth factor-18 (sprifermin) enhances microfracture-induced cartilage healing. J Orthop Res 2022; 40(3): 553-64.
[http://dx.doi.org/10.1002/jor.25063] [PMID: 33934397]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy