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Home / Equine Research Bank / Mol Ther / Implantation of rAAV5-IGF-I transduced autologous chondrocyt...
Molecular therapy : the journal of the American Society of Gene Therapy2014; 23(2); 363-373; doi: 10.1038/mt.2014.198

Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model.

Abstract: Cartilage injury often precipitates osteoarthritis which has driven research to bolster repair in cartilage impact damage. Autologous chondrocytes transduced with rAAV5-IGF-I were evaluated in chondral defects in a well-established large animal model. Cartilage was harvested from the talus of 24 horses; chondrocytes were isolated and stored frozen. Twenty million cells were cultured and transduced with 10(5) AAV vg/cell prior to implantation. Chondrocytes from eight horses were transduced with rAAV5-IGF-I, chondrocytes from eight horses with rAAV5-GFP, and chondrocytes from eight horses were not transduced. A 15 mm full-thickness chondral defect was created arthroscopically in the lateral trochlear ridge of the femur in both femoropatellar joints. Treated defects were filled with naive or gene-enhanced chondrocytes, in fibrin vehicle. Control defects in the opposite limb received fibrin alone. rAAV5-IGF-I transduced chondrocytes resulted in significantly better healing at 8 week arthroscopy and 8 month necropsy examination when compared to controls. At 8 months, defects implanted with cells expressing IGF-I had better histological scores compared to control defects and defects repaired with naive chondrocytes. This included increased chondrocyte predominance and collagen type II, both features of hyaline-like repair tissue. The equine model closely approximates human cartilage healing, indicating AAV-mediated genetic modification of chondrocytes may be clinically beneficial to humans.
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Publication Date: 2014-10-14 PubMed ID: 25311491PubMed Central: PMC4445609DOI: 10.1038/mt.2014.198Google Scholar: Lookup
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  • Journal Article
  • Research Support
  • Non-U.S. Gov't

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 is a study on the use of genetically modified chondrocytes (cartilage cells) for the improvement of cartilage repair in horses, which could have implications for human cartilage healing.

Research Methodology

  • To begin with, the researchers harvested cartilage from 24 horses, followed by isolating and freezing chondrocytes (cartilage cells).
  • Twenty million of these cells were cultured and genetically modified (transduced) by a method known as rAAV5-IGF-I.
  • Chondrocytes from eight horses were transduced with rAAV5-IGF-I, a type of viral vector used to deliver the growth factor IGF-I, eight horses received a rAAV5-GFP transduction and the cells from the remaining eight horses were not genetically modified.
  • Thereafter, the researchers created a full-thickness chondral (cartilage) defect in both knee joints of each horse. This defect was then treated with either naive (unmodified) or genetically modified chondrocytes in a fibrin vehicle (a protein used to deliver the cells).
  • The control group in the study consisted of horses in which the opposite knee received only fibrin, devoid of any chondrocytes.

Research Findings

  • They observed that rAAV5-IGF-I transduced chondrocytes significantly improved healing in terms of both time and quality at both 8 weeks post-treatment and after 8 months, as compared to the control group.
  • Defects in the knees that were implanted with cells expressing IGF-I had better histological scores as compared to control defects.
  • This included an increase in the number of chondrocytes (chondrocyte predominance) and more collagen type II synthesis which is a characteristics of hyaline-like tissue repair.

Implications of the Research

  • The researchers concluded that the horse model closely simulates human cartilage healing.
  • Therefore, their results indicate that genetic modification of chondrocytes using AAV-mediated approach could be beneficial for cartilage repair in humans as well.
  • The successful implementation of this technique has the potential to greatly improve treatments for cartilage injuries, which are often precursors to debilitating conditions such as osteoarthritis.

Cite This Article

APA
Ortved KF, Begum L, Mohammed HO, Nixon AJ. (2014). Implantation of rAAV5-IGF-I transduced autologous chondrocytes improves cartilage repair in full-thickness defects in the equine model. Mol Ther, 23(2), 363-373. https://doi.org/10.1038/mt.2014.198

Publication

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
NlmUniqueID: 100890581
Country: United States
Language: English
Volume: 23
Issue: 2
Pages: 363-373

Researcher Affiliations

Ortved, Kyla F
  • Comparative Orthopaedics Laboratory, Cornell University, Ithaca, New York, USA.
Begum, Laila
  • Comparative Orthopaedics Laboratory, Cornell University, Ithaca, New York, USA.
Mohammed, Hussni O
  • Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Nixon, Alan J
  • Comparative Orthopaedics Laboratory, Cornell University, Ithaca, New York, USA.

MeSH Terms

  • Animals
  • Arthroscopy
  • Cartilage, Articular
  • Cell Transplantation
  • Chondrocytes / metabolism
  • Chondrocytes / transplantation
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Horses
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Joint Diseases / metabolism
  • Joint Diseases / pathology
  • Joint Diseases / therapy
  • Regeneration
  • Synovial Fluid / metabolism
  • Time Factors
  • Transduction, Genetic
  • Transplantation, Autologous
  • Treatment Outcome
  • Wound Healing

Grant Funding

  • R01 AR055373 / NIAMS NIH HHS

References

This article includes 33 references
  1. Jackson DW, Lalor PA, Aberman HM, Simon TM. Spontaneous repair of full-thickness defects of articular cartilage in a goat model. A preliminary study.. J Bone Joint Surg Am 2001 Jan;83(1):53-64.
    pubmed: 11205859doi: 10.2106/00004623-200101000-00008google scholar: lookup
  2. Martin JA, Buckwalter JA. The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair.. J Bone Joint Surg Am 2003;85-A Suppl 2:106-10.
    pubmed: 12721352doi: 10.2106/00004623-200300002-00014google scholar: lookup
  3. Nehrer S, Spector M, Minas T. Histologic analysis of tissue after failed cartilage repair procedures.. Clin Orthop Relat Res 1999 Aug;(365):149-62.
    pubmed: 10627699doi: 10.1097/00003086-199908000-00020google scholar: lookup
  4. Steadman JR, Rodkey WG, Briggs KK. Microfracture to treat full-thickness chondral defects: surgical technique, rehabilitation, and outcomes.. J Knee Surg 2002 Summer;15(3):170-6.
    pubmed: 12152979
  5. Hangody L, Kish G, Kárpáti Z, Szerb I, Udvarhelyi I. Arthroscopic autogenous osteochondral mosaicplasty for the treatment of femoral condylar articular defects. A preliminary report.. Knee Surg Sports Traumatol Arthrosc 1997;5(4):262-7.
    pubmed: 9430578doi: 10.1007/s001670050061google scholar: lookup
  6. Marcacci M, Kon E, Zaffagnini S, Filardo G, Delcogliano M, Neri MP, Iacono F, Hollander AP. Arthroscopic second generation autologous chondrocyte implantation.. Knee Surg Sports Traumatol Arthrosc 2007 May;15(5):610-9.
    pubmed: 17372718doi: 10.1007/s00167-006-0265-9google scholar: lookup
  7. Basad E, Ishaque B, Bachmann G, Stürz H, Steinmeyer J. Matrix-induced autologous chondrocyte implantation versus microfracture in the treatment of cartilage defects of the knee: a 2-year randomised study.. Knee Surg Sports Traumatol Arthrosc 2010 Apr;18(4):519-27.
    pubmed: 20062969doi: 10.1007/s00167-009-1028-1google scholar: lookup
  8. 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 May;89(5):672-85.
    pubmed: 17540757doi: 10.1302/0301-620x.89b5.18343google scholar: lookup
  9. Elves MW, Zervas J. An investigation into the immunogenicity of various components of osteoarticular grafts.. Br J Exp Pathol 1974 Aug;55(4):344-51.
    pmc: PMC2072653pubmed: 4433468
  10. Adkisson HD, Milliman C, Zhang X, Mauch K, Maziarz RT, Streeter PR. Immune evasion by neocartilage-derived chondrocytes: Implications for biologic repair of joint articular cartilage.. Stem Cell Res 2010 Jan;4(1):57-68.
    pubmed: 19880363doi: 10.1016/j.scr.2009.09.004google scholar: lookup
  11. Verschure PJ, van Marle J, Joosten LA, van den Berg WB. Chondrocyte IGF-1 receptor expression and responsiveness to IGF-1 stimulation in mouse articular cartilage during various phases of experimentally induced arthritis.. Ann Rheum Dis 1995 Aug;54(8):645-53.
    pmc: PMC1009962pubmed: 7677441doi: 10.1136/ard.54.8.645google scholar: lookup
  12. 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 Mar;84(2):276-88.
    pubmed: 11922373doi: 10.1302/0301-620x.84b2.11167google scholar: lookup
  13. Fortier LA, Lust G, Mohammed HO, Nixon AJ. Coordinate upregulation of cartilage matrix synthesis in fibrin cultures supplemented with exogenous insulin-like growth factor-I.. J Orthop Res 1999 Jul;17(4):467-74.
    pubmed: 10459751doi: 10.1002/jor.1100170403google scholar: lookup
  14. Tyler JA. Insulin-like growth factor 1 can decrease degradation and promote synthesis of proteoglycan in cartilage exposed to cytokines.. Biochem J 1989 Jun 1;260(2):543-8.
    pmc: PMC1138702pubmed: 2788408doi: 10.1042/bj2600543google scholar: lookup
  15. Fosang AJ, Tyler JA, Hardingham TE. Effect of interleukin-1 and insulin like growth factor-1 on the release of proteoglycan components and hyaluronan from pig articular cartilage in explant culture.. Matrix 1991 Feb;11(1):17-24.
    pubmed: 2027327doi: 10.1016/s0934-8832(11)80223-4google scholar: lookup
  16. Ortved KF, Nixon AJ, Mohammed HO, Fortier LA. Treatment of subchondral cystic lesions of the medial femoral condyle of mature horses with growth factor enhanced chondrocyte grafts: a retrospective study of 49 cases.. Equine Vet J 2012 Sep;44(5):606-13.
    pubmed: 22128804doi: 10.1111/j.2042-3306.2011.00510.xgoogle scholar: lookup
  17. Daya S, Berns KI. Gene therapy using adeno-associated virus vectors.. Clin Microbiol Rev 2008 Oct;21(4):583-93.
    pmc: PMC2570152pubmed: 18854481doi: 10.1128/cmr.00008-08google scholar: lookup
  18. McCarty DM, Monahan PE, Samulski RJ. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis.. Gene Ther 2001 Aug;8(16):1248-54.
    pubmed: 11509958doi: 10.1038/sj.gt.3301514google scholar: lookup
  19. Begum L, Ortved KF, Nixon AJ.2010AAV-5 provides more efficient transgene expression in chondrocytes grown in adherent and suspension cultureTrans Orthop Res Soc 56th Ann Mtg, Seattle, WA.
  20. Madry H, Padera R, Seidel J, Langer R, Freed LE, Trippel SB, Vunjak-Novakovic G. Gene transfer of a human insulin-like growth factor I cDNA enhances tissue engineering of cartilage.. Hum Gene Ther 2002 Sep 1;13(13):1621-30.
    pubmed: 12228017doi: 10.1089/10430340260201716google scholar: lookup
  21. Nixon AJ, Saxer RA, Brower-Toland BD. Exogenous insulin-like growth factor-I stimulates an autoinductive IGF-I autocrine/paracrine response in chondrocytes.. J Orthop Res 2001 Jan;19(1):26-32.
    pubmed: 11332617doi: 10.1016/s0736-0266(00)00013-9google scholar: lookup
  22. 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-1.. Am J Vet Res 2002 Feb;63(2):301-5.
    pubmed: 11843134doi: 10.2460/ajvr.2002.63.301google scholar: lookup
  23. Pearce SG, Hurtig MB, Clarnette R, Kalra M, Cowan B, Miniaci A. An investigation of 2 techniques for optimizing joint surface congruency using multiple cylindrical osteochondral autografts.. Arthroscopy 2001 Jan;17(1):50-5.
    pubmed: 11154367doi: 10.1053/jars.2001.19966google scholar: lookup
  24. Shakibaei M, Seifarth C, John T, Rahmanzadeh M, Mobasheri A. Igf-I extends the chondrogenic potential of human articular chondrocytes in vitro: molecular association between Sox9 and Erk1/2.. Biochem Pharmacol 2006 Nov 30;72(11):1382-95.
    pubmed: 17010943doi: 10.1016/j.bcp.2006.08.022google scholar: lookup
  25. Barbero A, Grogan S, Schäfer D, Heberer M, Mainil-Varlet P, Martin I. Age related changes in human articular chondrocyte yield, proliferation and post-expansion chondrogenic capacity.. Osteoarthritis Cartilage 2004 Jun;12(6):476-84.
    pubmed: 15135144doi: 10.1016/j.joca.2004.02.010google scholar: lookup
  26. Oshin AO, Caporali E, Byron CR, Stewart AA, Stewart MC. Phenotypic maintenance of articular chondrocytes in vitro requires BMP activity.. Vet Comp Orthop Traumatol 2007;20(3):185-91.
    pubmed: 17846684doi: 10.1160/vcot-06-07-0061google scholar: lookup
  27. Takahashi T, Ogasawara T, Asawa Y, Mori Y, Uchinuma E, Takato T, Hoshi K. Three-dimensional microenvironments retain chondrocyte phenotypes during proliferation culture.. Tissue Eng 2007 Jul;13(7):1583-92.
    pubmed: 17630901doi: 10.1089/ten.2006.0322google scholar: lookup
  28. Schubert T, Anders S, Neumann E, Schölmerich J, Hofstädter F, Grifka J, Müller-Ladner U, Libera J, Schedel J. Long-term effects of chondrospheres on cartilage lesions in an autologous chondrocyte implantation model as investigated in the SCID mouse model.. Int J Mol Med 2009 Apr;23(4):455-60.
    pubmed: 19288020doi: 10.3892/ijmm_00000151google scholar: lookup
  29. 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(3):142-6.
    pubmed: 16971996
  30. Nixon AJ, Lust G, Vernier-Singer M. Isolation, propagation, and cryopreservation of equine articular chondrocytes.. Am J Vet Res 1992 Dec;53(12):2364-70.
    pubmed: 1476323
  31. 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 Jul;21(4):573-83.
    pubmed: 12798054doi: 10.1016/s0736-0266(02)00264-4google scholar: lookup
  32. Dresdale A, Rose EA, Jeevanandam V, Reemtsma K, Bowman FO, Malm JR. Preparation of fibrin glue from single-donor fresh-frozen plasma.. Surgery 1985 Jun;97(6):750-5.
    pubmed: 3873716
  33. Farndale RW, Sayers CA, Barrett AJ. A direct spectrophotometric microassay for sulfated glycosaminoglycans in cartilage cultures.. Connect Tissue Res 1982;9(4):247-8.
    pubmed: 6215207doi: 10.3109/03008208209160269google scholar: lookup

Citations

This article has been cited 18 times.
  1. Li X, Shen L, Deng Z, Huang Z. New treatment for osteoarthritis: Gene therapy.. Precis Clin Med 2023 Jun;6(2):pbad014.
    doi: 10.1093/pcmedi/pbad014pubmed: 37333626google scholar: lookup
  2. Nagelli CV, Evans CH, De la Vega RE. Gene Delivery to Chondrocytes.. Adv Exp Med Biol 2023;1402:95-105.
    doi: 10.1007/978-3-031-25588-5_7pubmed: 37052849google scholar: lookup
  3. Thampi P, Samulski RJ, Grieger JC, Phillips JN, McIlwraith CW, Goodrich LR. Gene therapy approaches for equine osteoarthritis.. Front Vet Sci 2022;9:962898.
    doi: 10.3389/fvets.2022.962898pubmed: 36246316google scholar: lookup
  4. Watson-Levings RS, Palmer GD, Levings PP, Dacanay EA, Evans CH, Ghivizzani SC. Gene Therapy in Orthopaedics: Progress and Challenges in Pre-Clinical Development and Translation.. Front Bioeng Biotechnol 2022;10:901317.
    doi: 10.3389/fbioe.2022.901317pubmed: 35837555google scholar: lookup
  5. Wen C, Xu L, Xu X, Wang D, Liang Y, Duan L. Insulin-like growth factor-1 in articular cartilage repair for osteoarthritis treatment.. Arthritis Res Ther 2021 Oct 30;23(1):277.
    doi: 10.1186/s13075-021-02662-0pubmed: 34717735google scholar: lookup
  6. Lin MJ, Lu MC, Chan YC, Huang YF, Chang HY. An Insulin-like Growth Factor-1 Conjugated Bombyx mori Silk Fibroin Film for Diabetic Wound Healing: Fabrication, Physicochemical Property Characterization, and Dosage Optimization In Vitro and In Vivo.. Pharmaceutics 2021 Sep 13;13(9).
    doi: 10.3390/pharmaceutics13091459pubmed: 34575535google scholar: lookup
  7. Trompeter N, Gardinier JD, DeBarros V, Boggs M, Gangadharan V, Cain WJ, Hurd L, Duncan RL. Insulin-like growth factor-1 regulates the mechanosensitivity of chondrocytes by modulating TRPV4.. Cell Calcium 2021 Nov;99:102467.
    doi: 10.1016/j.ceca.2021.102467pubmed: 34530313google scholar: lookup
  8. Szwedowski D, Szczepanek J, Paczesny Ł, Pękała P, Zabrzyński J, Kruczyński J. Genetics in Cartilage Lesions: Basic Science and Therapy Approaches.. Int J Mol Sci 2020 Jul 30;21(15).
    doi: 10.3390/ijms21155430pubmed: 32751537google scholar: lookup
  9. Urich J, Cucchiarini M, Rey-Rico A. Therapeutic Delivery of rAAV sox9 via Polymeric Micelles Counteracts the Effects of Osteoarthritis-Associated Inflammatory Cytokines in Human Articular Chondrocytes.. Nanomaterials (Basel) 2020 Jun 25;10(6).
    doi: 10.3390/nano10061238pubmed: 32630578google scholar: lookup
  10. Fugazzola MC, van Weeren PR. Surgical osteochondral defect repair in the horse-a matter of form or function?. Equine Vet J 2020 Jul;52(4):489-499.
    doi: 10.1111/evj.13231pubmed: 31958175google scholar: lookup
  11. Venkatesan JK, Rey-Rico A, Cucchiarini M. Current Trends in Viral Gene Therapy for Human Orthopaedic Regenerative Medicine.. Tissue Eng Regen Med 2019 Aug;16(4):345-355.
    doi: 10.1007/s13770-019-00179-xpubmed: 31413939google scholar: lookup
  12. McClain AK, McCarrel TM. The effect of four different freezing conditions and time in frozen storage on the concentration of commonly measured growth factors and enzymes in equine platelet-rich plasma over six months.. BMC Vet Res 2019 Aug 14;15(1):292.
    doi: 10.1186/s12917-019-2040-4pubmed: 31412868google scholar: lookup
  13. Davies RL, Kuiper NJ. Regenerative Medicine: A Review of the Evolution of Autologous Chondrocyte Implantation (ACI) Therapy.. Bioengineering (Basel) 2019 Mar 13;6(1).
    doi: 10.3390/bioengineering6010022pubmed: 30871236google scholar: lookup
  14. Cucchiarini M, Madry H. Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair.. Nat Rev Rheumatol 2019 Jan;15(1):18-29.
    doi: 10.1038/s41584-018-0125-2pubmed: 30514957google scholar: lookup
  15. Zhang Y, Peng X, Song W, Sun Y, Wang L, Li Q, Zhao R. [Effects of microRNA-140 gene transfection with nucleus localization signal linked nucleic kinase substrate short peptide conjugated chitosan on rabbit articular chondrocytes].. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2017 Oct 15;31(10):1256-1261.
    doi: 10.7507/1002-1892.201705088pubmed: 29806331google scholar: lookup
  16. Rey-Rico A, Cucchiarini M. Recent tissue engineering-based advances for effective rAAV-mediated gene transfer in the musculoskeletal system.. Bioengineered 2016 Apr;7(3):175-88.
    doi: 10.1080/21655979.2016.1187347pubmed: 27221233google scholar: lookup
  17. Natenstedt J, Kok AC, Dankelman J, Tuijthof GJ. What quantitative mechanical loading stimulates in vitro cultivation best?. J Exp Orthop 2015 Dec;2(1):15.
    doi: 10.1186/s40634-015-0029-xpubmed: 26914883google scholar: lookup
  18. Evans CH, Huard J. Gene therapy approaches to regenerating the musculoskeletal system.. Nat Rev Rheumatol 2015 Apr;11(4):234-42.
    doi: 10.1038/nrrheum.2015.28pubmed: 25776949google scholar: lookup
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