Recombinant adeno-associated virus-based gene therapy combined with tissue engineering for musculoskeletal regenerative medicine
Recombinant adeno-associated viral (rAAV) vector-mediated gene delivery is a novel molecular therapeutic approach for musculoskeletal disorders which achieves tissue regeneration by delivering a transgene to the impaired tissue. In recent years, substantial scientific progress in rAAV gene therapy has led to several clinical trials for human musculoskeletal diseases. Nevertheless, there are still limitations in developing an optimal gene therapy model due to the low transduction efficiency and fast degradation of the gene vectors. To overcome the challenges of rAAV gene therapy, tissue engineering combined with gene therapy has emerged as a more promising alternative. An rAAV viral vector incorporated into a biomaterial has a more controlled gene expression, lower immune response, and higher efficiency. A number of biomaterials and architectures have been combined with rAAV viral vectors, each having its own advantages and limitations. This review aims to give a broad introduction to combinatorial therapy and the recent progress this new technology has offered.
Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.
1. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018, 392, 1789-1858.
2. Langer, R.; Vacanti, J. P. Tissue engineering. Science. 1993, 260, 920-926.
3. Narayanan, G.; Vernekar, V. N.; Kuyinu, E. L.; Laurencin, C. T. Poly (lactic acid)-based biomaterials for orthopaedic regenerative engineering. Adv Drug Deliv Rev. 2016, 107, 247-276.
4. Grol, M. W.; Lee, B. H. Gene therapy for repair and regeneration of bone and cartilage. Curr Opin Pharmacol. 2018, 40, 59-66.
5. Mesure, B.; Menu, P.; Venkatesan, J. K.; Cucchiarini, M.; Velot, É. Biomaterials and gene therapy: A smart combination for MSC musculoskeletal engineering. Curr Stem Cell Res Ther. 2019, 14, 337-343.
6. Yazici, C.; Schwarz, E. M. Regenerative therapy for the musculoskeletal system using recombinant adeno-associated viral vectors. In Advances in gene delivery for bone allografts. Cucchiarini, M.; Madry, H., eds. Research Signpost: Thiruvananthapuram. 2011, pp 109-126.
7. Gaharwar, A. K.; Singh, I.; Khademhosseini, A. Engineered biomaterials for in situ tissue regeneration. Nat Rev Mater. 2020, 5, 686-705.
8. Bulaklak, K.; Xiao, X. Therapeutic advances in musculoskeletal AAV targeting approaches. Curr Opin Pharmacol. 2017, 34, 56-63.
9. Xiao, X.; Li, J.; Samulski, R. J. Efficient long-term gene transfer into muscle tissue of immunocompetent mice by adeno-associated virus vector. J Virol. 1996, 70, 8098-8108.
10. Kruzik, A.; Fetahagic, D.; Hartlieb, B.; Dorn, S.; Koppensteiner, H.; Horling, F. M.; Scheiflinger, F.; Reipert, B. M.; de la Rosa, M. Prevalence of anti-adeno-associated virus immune responses in international cohorts of healthy donors. Mol Ther Methods Clin Dev. 2019, 14, 126-133.
11. Wang, D.; Tai, P. W. L.; Gao, G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019, 18, 358-378.
12. Naso, M. F.; Tomkowicz, B.; Perry, W. L. 3rd; Strohl, W. R. Adeno-associated virus (AAV) as a vector for gene therapy. Biodrugs. 2017, 31, 317-334.
13. Levy, H. C.; Hulvey, D.; Adamson-Small, L.; Jn-Simon, N.; Prima, V.; Rivkees, S.; Hobbs, J. A. Improved cell-specificity of adeno-associated viral vectors for medullary thyroid carcinoma using calcitonin gene regulatory elements. PLoS One. 2020, 15, e0228005.
14. Li, C.; Samulski, R. J. Engineering adeno-associated virus vectors for gene therapy. Nat Rev Genet. 2020, 21, 255-272.
15. Hickey, D. G.; Edwards, T. L.; Barnard, A. R.; Singh, M. S.; de Silva, S. R.; McClements, M. E.; Flannery, J. G.; Hankins, M. W.; MacLaren, R. E. Tropism of engineered and evolved recombinant AAV serotypes in the rd1 mouse and ex vivo primate retina. Gene Ther. 2017, 24, 787-800.
16. Muraine, L.; Bensalah, M.; Dhiab, J.; Cordova, G.; Arandel, L.; Marhic, A.; Chapart, M.; Vasseur, S.; Benkhelifa-Ziyyat, S.; Bigot, A.; Butler-Browne, G.; Mouly, V.; Negroni, E.; Trollet, C. Transduction efficiency of adeno-associated virus serotypes after local injection in mouse and human skeletal muscle. Hum Gene Ther. 2020, 31, 233-240.
17. Pacak, C. A.; Mah, C. S.; Thattaliyath, B. D.; Conlon, T. J.; Lewis, M. A.; Cloutier, D. E.; Zolotukhin, I.; Tarantal, A. F.; Byrne, B. J. Recombinant adeno-associated virus serotype 9 leads to preferential cardiac transduction in vivo. Circ Res. 2006, 99, e3-9.
18. Liu, Z.; Klose, K.; Neuber, S.; Jiang, M.; Gossen, M.; Stamm, C. Comparative analysis of adeno-associated virus serotypes for gene transfer in organotypic heart slices. J Transl Med. 2020, 18, 437.
19. Majowicz, A.; Salas, D.; Zabaleta, N.; Rodríguez-Garcia, E.; González-Aseguinolaza, G.; Petry, H.; Ferreira, V. Successful repeated hepatic gene delivery in mice and non-human primates achieved by sequential administration of AAV5(ch) and AAV1. Mol Ther. 2017, 25, 1831-1842.
20. Lee, S. H.; Kim, S.; Lee, N.; Lee, J.; Yu, S. S.; Kim, J. H.; Kim, S. Intrathecal delivery of recombinant AAV1 encoding hepatocyte growth factor improves motor functions and protects neuromuscular system in the nerve crush and SOD1-G93A transgenic mouse models. Acta Neuropathol Commun. 2019, 7, 96.
21. Clinical intramuscular gene transfer of rAAV1.CMV.huFollistatin344 trial to patients with duchenne muscular dystrophy. https://clinicaltrials.gov/ct2/show/NCT02354781. Accessed by January 2015.
22. Corti, M.; Liberati, C.; Smith, B. K.; Lawson, L. A.; Tuna, I. S.; Conlon, T. J.; Coleman, K. E.; Islam, S.; Herzog, R. W.; Fuller, D. D.; Collins, S. W.; Byrne, B. J. Safety of intradiaphragmatic delivery of adeno-associated virus-mediated alpha-glucosidase (rAAV1-CMV-hGAA) gene therapy in children affected by Pompe disease. Hum Gene Ther Clin Dev. 2017, 28, 208-218.
23. Zhou, X.; Shen, L.; Liu, L.; Wang, C.; Qi, W.; Zhao, A.; Wu, X.; Li, B. Preclinical safety evaluation of recombinant adeno-associated virus 2 vector encoding human tumor necrosis factor receptor-immunoglobulin Fc fusion gene. Hum Vaccin Immunother. 2016, 12, 732-739.
24. Chen, Z.; Fan, G.; Li, A.; Yuan, J.; Xu, T. rAAV2-retro enables extensive and high-efficient transduction of lower motor neurons following intramuscular injection. Mol Ther Methods Clin Dev. 2020, 17, 21-33.
25. AAV2-GDNF for advanced Parkinson’s disease. https://clinicaltrials.gov/ct2/show/NCT01621581. Accessed by March 13, 2013.
26. Efficacy and safety of BIIB111 for the treatment of choroideremia (STAR). https://clinicaltrials.gov/ct2/show/NCT03496012. Accessed by December 11, 2017.
27. Safety and dose escalation study of AAV2-hCHM in subjects with CHM (Choroideremia) gene mutations. https://clinicaltrials.gov/ct2/show/NCT02341807. Accessed by January 2015.
28. Long-term safety and efficacy follow-up of AAV2-REP1 for the treatment of choroideremia (SOLSTICE). https://clinicaltrials.gov/ct2/show/NCT03584165. Accessed by June 4, 2018.
29. Haggerty, D. L.; Grecco, G. G.; Reeves, K. C.; Atwood, B. Adeno-associated viral vectors in neuroscience research. Mol Ther Methods Clin Dev. 2020, 17, 69-82.
30. Li, J.; Wen, A. M.; Potla, R.; Benshirim, E.; Seebarran, A.; Benz, M. A.; Henry, O. Y. F.; Matthews, B. D.; Prantil-Baun, R.; Gilpin, S. E.; Levy, O.; Ingber, D. E. AAV-mediated gene therapy targeting TRPV4 mechanotransduction for inhibition of pulmonary vascular leakage. APL Bioeng. 2019, 3, 046103.
31. Aalbers, C. J.; Bevaart, L.; Loiler, S.; de Cortie, K.; Wright, J. F.; Mingozzi, F.; Tak, P. P.; Vervoordeldonk, M. J. Preclinical potency and biodistribution studies of an AAV 5 vector expressing human interferon-β (ART-I02) for local treatment of patients with rheumatoid arthritis. PLoS One. 2015, 10, e0130612.
32. Six month lead-in study to evaluate prospective efficacy and safety data of current FIX prophylaxis replacement therapy in adult hemophilia B subjects (FIX:C≤2%) or current FVIII Prophylaxis replacement therapy in adult hemophilia A subjects (FVIII:C≤1%). https://clinicaltrials.gov/ct2/show/NCT03587116. Accessed by July 26, 2018.
33. Study to evaluate the efficacy and safety of PF-07055480 in moderately severe to severe hemophilia A adults (AFFINE). https://clinicaltrials.gov/ct2/show/NCT04370054. Accessed by August 18, 2020.
34. Rubin, J. D.; Nguyen, T. V.; Allen, K. L.; Ayasoufi, K.; Barry, M. A. Comparison of gene delivery to the kidney by adenovirus, adeno-associated virus, and lentiviral vectors after intravenous and direct kidney injections. Hum Gene Ther. 2019, 30, 1559-1571.
35. Taymans, J. M.; Vandenberghe, L. H.; Haute, C. V.; Thiry, I.; Deroose, C. M.; Mortelmans, L.; Wilson, J. M.; Debyser, Z.; Baekelandt, V. Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther. 2007, 18, 195-206.
36. Shao, W.; Pei, X.; Cui, C.; Askew, C.; Dobbins, A.; Chen, X.; Abajas, Y. L.; Gerber, D. A.; Samulski, R. J.; Nichols, T. C.; Li, C. Superior human hepatocyte transduction with adeno-associated virus vector serotype 7. Gene Ther. 2019, 26, 504-514.
37. Chen, V. P.; Gao, Y.; Geng, L.; Steele, M.; Jenks, N.; Peng, K. W.; Brimijoin, S. Systemic safety of a recombinant AAV8 vector for human cocaine hydrolase gene therapy: A good laboratory practice preclinical study in mice. Hum Gene Ther. 2020, 31, 70-79.
38. Nathwani, A. C.; Reiss, U. M.; Tuddenham, E. G.; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, M.; Shen, Y. M.; Halka, K. G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K. A.; Allay, J.; Kay, M. A.; Ng, C. Y.; Zhou, J.; Cancio, M.; Morton, C. L.; Gray, J. T.; Srivastava, D.; Nienhuis, A. W.; Davidoff, A. M. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014, 371, 1994-2004.
39. Safety and efficacy of a single subretinal injection of rAAV.hCNGA3 in patients with CNGA3-linked achromatopsia. https://clinicaltrials.gov/ct2/show/NCT02610582. Accessed by November 2015.
40. Gu, X.; Matsumura, Y.; Tang, Y.; Roy, S.; Hoff, R.; Wang, B.; Wagner, W. R. Sustained viral gene delivery from a micro-fibrous, elastomeric cardiac patch to the ischemic rat heart. Biomaterials. 2017, 133, 132-143.
41. Pattali, R.; Mou, Y.; Li, X. J. AAV9 Vector: a Novel modality in gene therapy for spinal muscular atrophy. Gene Ther. 2019, 26, 287-295.
42. AAVRh.10 administered to children with late infantile neuronal ceroid lipofuscinosis. https://clinicaltrials.gov/ct2/show/NCT01414985. Accessed by April 15, 2010.
43. Study of AAVrh10-h.SGSH gene therapy in patients with mucopolysaccharidosis type IIIA (MPS IIIA) (AAVance). https://clinicaltrials.gov/ct2/show/NCT03612869. Accessed by December 17, 2018.
44. Wang, B.; Li, J.; Fu, F. H.; Chen, C.; Zhu, X.; Zhou, L.; Jiang, X.; Xiao, X. Construction and analysis of compact muscle-specific promoters for AAV vectors. Gene Ther. 2008, 15, 1489-1499.
45. Charbord, P. Mesenchymal stem cell characterization. In Regenerative medicine and cell therapy. Stoltz, J. F., ed. IOS Press. 2012, pp 27-35.
46. Murphy, M.; Curtin, C.; Duffy, G.; Kavanagh, C.; Barry, F. Mesenchymal stem cells in regenerative medicine. In Regenerative medicine and cell therapy. Stoltz, J. F., ed. IOS Press. 2012, pp 51-61.
47. Caplan, A. I. Mesenchymal stem cells. J Orthop Res. 1991, 9, 641-650.
48. Tuan, R. S.; Boland, G.; Tuli, R. Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther. 2003, 5, 32-45.
49. Colombini, A.; Perucca Orfei, C.; Kouroupis, D.; Ragni, E.; De Luca, P.; Viganò, M.; Correa, D.; de Girolamo, L. Mesenchymal stem cells in the treatment of articular cartilage degeneration: New biological insights for an old-timer cell. Cytotherapy. 2019, 21, 1179-1197.
50. Qi, Y.; Feng, G.; Yan, W. Mesenchymal stem cell-based treatment for cartilage defects in osteoarthritis. Mol Biol Rep. 2012, 39, 5683-5689.
51. Huang, S.; Xu, L.; Zhang, Y.; Sun, Y.; Li, G. Systemic and local administration of allogeneic bone marrow-derived mesenchymal stem cells promotes fracture healing in rats. Cell Transplant. 2015, 24, 2643-2655.
52. Maxson, S.; Lopez, E. A.; Yoo, D.; Danilkovitch-Miagkova, A.; Leroux, M. A. Concise review: Role of mesenchymal stem cells in wound repair. Stem Cells Transl Med. 2012, 1, 142-149.
53. Lee, D. E.; Ayoub, N.; Agrawal, D. K. Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther. 2016, 7, 37.
54. Einhorn, T. A.; Majeska, R. J.; Mohaideen, A.; Kagel, E. M.; Bouxsein, M. L.; Turek, T. J.; Wozney, J. M. A single percutaneous injection of recombinant human bone morphogenetic protein-2 accelerates fracture repair. J Bone Joint Surg Am. 2003, 85, 1425-1435.
55. Bond, A. M.; Bhalala, O. G.; Kessler, J. A. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev Neurobiol. 2012, 72, 1068-1084.
56. Xu, H. H.; Liu, S. H.; Guo, Q. F.; Liu, Q. H.; Li, X. Y. Osteogenesis induced in goat bone marrow progenitor cells by recombinant adenovirus coexpressing bone morphogenetic protein 2 and basic fibroblast growth factor. Braz J Med Biol Res. 2013, 46, 809-814.
57. Zhang, C.; Meng, C.; Guan, D.; Ma, F. BMP2 and VEGF165 transfection to bone marrow stromal stem cells regulate osteogenic potential in vitro. Medicine (Baltimore). 2018, 97, e9787.
58. Lin, H.; Tang, Y.; Lozito, T. P.; Oyster, N.; Wang, B.; Tuan, R. S. Efficient in vivo bone formation by BMP-2 engineered human mesenchymal stem cells encapsulated in a projection stereolithographically fabricated hydrogel scaffold. Stem Cell Res Ther. 2019, 10, 254.
59. Evans, C. H.; Ghivizzani, S. C.; Robbins, P. D. Gene delivery to joints by intra-articular injection. Hum Gene Ther. 2018, 29, 2-14.
60. Nidetz, N. F.; McGee, M. C.; Tse, L. V.; Li, C.; Cong, L.; Li, Y.; Huang, W. Adeno-associated viral vector-mediated immune responses: Understanding barriers to gene delivery. Pharmacol Ther. 2020, 207, 107453.
61. Ronzitti, G.; Gross, D. A.; Mingozzi, F. Human immune responses to adeno-associated virus (AAV) vectors. Front Immunol. 2020, 11, 670.
62. Buck, T. M.; Wijnholds, J. Recombinant Adeno-Associated Viral Vectors (rAAV) - Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays. Int J Mol Sci. 2020, 21, 4197.
63. O’Brien, F. J. Biomaterials & scaffolds for tissue engineering. Mater Today. 2011, 14, 88-95.
64. Pina, S.; Ribeiro, V. P.; Marques, C. F.; Maia, F. R.; Silva, T. H.; Reis, R. L.; Oliveira, J. M. Scaffolding strategies for tissue engineering and regenerative medicine applications. Materials (Basel). 2019, 12, 1824.
65. BaoLin, G.; Ma, P. X. Synthetic biodegradable functional polymers for tissue engineering: a brief review. Sci China Chem. 2014, 57, 490-500.
66. D’Mello, S.; Atluri, K.; Geary, S. M.; Hong, L.; Elangovan, S.; Salem, A. K. Bone regeneration using gene-activated matrices. AAPS J. 2017, 19, 43-53.
67. Yuan, T.; Zhang, L.; Li, K.; Fan, H.; Fan, Y.; Liang, J.; Zhang, X. Collagen hydrogel as an immunomodulatory scaffold in cartilage tissue engineering. J Biomed Mater Res B Appl Biomater. 2014, 102, 337-344.
68. Mano, J. F.; Silva, G. A.; Azevedo, H. S.; Malafaya, P. B.; Sousa, R. A.; Silva, S. S.; Boesel, L. F.; Oliveira, J. M.; Santos, T. C.; Marques, A. P.; Neves, N. M.; Reis, R. L. Natural origin biodegradable systems in tissue engineering and regenerative medicine: present status and some moving trends. J R Soc Interface. 2007, 4, 999-1030.
69. Cen, L.; Liu, W.; Cui, L.; Zhang, W.; Cao, Y. Collagen tissue engineering: development of novel biomaterials and applications. Pediatr Res. 2008, 63, 492-496.
70. Sun, K.; Lin, H.; Tang, Y.; Xiang, S.; Xue, J.; Yin, W.; Tan, J.; Peng, H.; Alexander, P. G.; Tuan, R. S.; Wang, B. Injectable BMP-2 gene-activated scaffold for the repair of cranial bone defect in mice. Stem Cells Transl Med. 2020, 9, 1631-1642.
71. Bambole, V.; Yakhmi, J. V. Chapter 14 - Tissue engineering: Use of electrospinning technique for recreating physiological functions. In Nanobiomaterials in soft tissue engineering. Grumezescu, A. M., ed. William Andrew Publishing. 2016, pp 387-455.
72. Lee, H. H.; Haleem, A. M.; Yao, V.; Li, J.; Xiao, X.; Chu, C. R. Release of bioactive adeno-associated virus from fibrin scaffolds: effects of fibrin glue concentrations. Tissue Eng Part A. 2011, 17, 1969-1978.
73. Gao, X.; Usas, A.; Tang, Y.; Lu, A.; Tan, J.; Schneppendahl, J.; Kozemchak, A. M.; Wang, B.; Cummins, J. H.; Tuan, R. S.; Huard, J. A comparison of bone regeneration with human mesenchymal stem cells and muscle-derived stem cells and the critical role of BMP. Biomaterials. 2014, 35, 6859-6870.
74. Gao, X.; Usas, A.; Lu, A.; Tang, Y.; Wang, B.; Chen, C. W.; Li, H.; Tebbets, J. C.; Cummins, J. H.; Huard, J. BMP2 is superior to BMP4 for promoting human muscle-derived stem cell-mediated bone regeneration in a critical-sized calvarial defect model. Cell Transplant. 2013, 22, 2393-2408.
75. Lin, H.; Tang, Y.; Lozito, T. P.; Oyster, N.; Kang, R. B.; Fritch, M. R.; Wang, B.; Tuan, R. S. Projection stereolithographic fabrication of BMP-2 gene-activated matrix for bone tissue engineering. Sci Rep. 2017, 7, 11327.
76. Venkatesan, J. K.; Falentin-Daudré, C.; Leroux, A.; Migonney, V.; Cucchiarini, M. Biomaterial-guided recombinant adeno-associated virus delivery from poly(sodium styrene sulfonate)-grafted poly(ε-caprolactone) films to target human bone marrow aspirates. Tissue Eng Part A. 2020, 26, 450-459.
77. Salehi, S.; Czugala, M.; Stafiej, P.; Fathi, M.; Bahners, T.; Gutmann, J. S.; Singer, B. B.; Fuchsluger, T. A. Poly (glycerol sebacate)-poly (ε-caprolactone) blend nanofibrous scaffold as intrinsic bio- and immunocompatible system for corneal repair. Acta Biomater. 2017, 50, 370-380.
78. Xue, J.; Lin, H.; Bean, A.; Tang, Y.; Tan, J.; Tuan, R. S.; Wang, B. One-step fabrication of bone morphogenetic protein-2 gene-activated porous poly-l-lactide scaffold for bone induction. Mol Ther Methods Clin Dev. 2017, 7, 50-59.
79. Rey-Rico, A.; Venkatesan, J. K.; Frisch, J.; Schmitt, G.; Monge-Marcet, A.; Lopez-Chicon, P.; Mata, A.; Semino, C.; Madry, H.; Cucchiarini, M. Effective and durable genetic modification of human mesenchymal stem cells via controlled release of rAAV vectors from self-assembling peptide hydrogels with maintained differentiation potency. Acta Biomater. 2015, 18, 118-127.
80. Patenaude, M.; Campbell, S.; Kinio, D.; Hoare, T. Tuning gelation time and morphology of injectable hydrogels using ketone-hydrazide cross-linking. Biomacromolecules. 2014, 15, 781-790.
81. Wang, Y.; Adokoh, C. K.; Narain, R. Recent development and biomedical applications of self-healing hydrogels. Expert Opin Drug Deliv. 2018, 15, 77-91.
82. Shen, H.; Lin, H.; Sun, A. X.; Song, S.; Wang, B.; Yang, Y.; Dai, J.; Tuan, R. S. Acceleration of chondrogenic differentiation of human mesenchymal stem cells by sustained growth factor release in 3D graphene oxide incorporated hydrogels. Acta Biomater. 2020, 105, 44-55.
83. Lin, H.; Cheng, A. W.; Alexander, P. G.; Beck, A. M.; Tuan, R. S. Cartilage tissue engineering application of injectable gelatin hydrogel with in situ visible-light-activated gelation capability in both air and aqueous solution. Tissue Eng Part A. 2014, 20, 2402-2411.
84. Chai, Q.; Jiao, Y.; Yu, X. Hydrogels for biomedical applications: Their characteristics and the mechanisms behind them. Gels. 2017, 3, 6.
85. Ahmed, E. M. Hydrogel: Preparation, characterization, and applications: A review. J Adv Res. 2015, 6, 105-121.
86. Madrigal, J. L.; Shams, S.; Stilhano, R. S.; Silva, E. A. Characterizing the encapsulation and release of lentivectors and adeno-associated vectors from degradable alginate hydrogels. Biomater Sci. 2019, 7, 645-656.
87. Rey-Rico, A.; Madry, H.; Cucchiarini, M. Hydrogel-based controlled delivery systems for articular cartilage repair. Biomed Res Int. 2016, 2016, 1215263.
88. Alvarez-Rivera, F.; Rey-Rico, A.; Venkatesan, J. K.; Diaz-Gomez, L.; Cucchiarini, M.; Concheiro, A.; Alvarez-Lorenzo, C. Controlled release of rAAV vectors from APMA-functionalized contact lenses for corneal gene therapy. Pharmaceutics. 2020, 12, 335.
89. Jackman, S. L.; Chen, C. H.; Chettih, S. N.; Neufeld, S. Q.; Drew, I. R.; Agba, C. K.; Flaquer, I.; Stefano, A. N.; Kennedy, T. J.; Belinsky, J. E.; Roberston, K.; Beron, C. C.; Sabatini, B. L.; Harvey, C. D.; Regehr, W. G. Silk fibroin films facilitate single-step targeted expression of optogenetic proteins. Cell Rep. 2018, 22, 3351-3361.
90. Gamie, Z.; Tran, G. T.; Vyzas, G.; Korres, N.; Heliotis, M.; Mantalaris, A.; Tsiridis, E. Stem cells combined with bone graft substitutes in skeletal tissue engineering. Expert Opin Biol Ther. 2012, 12, 713-729.
91. Bruder, S. P.; Fink, D. J.; Caplan, A. I. Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. J Cell Biochem. 1994, 56, 283-294.
92. Dupont, K. M.; Boerckel, J. D.; Stevens, H. Y.; Diab, T.; Kolambkar, Y. M.; Takahata, M.; Schwarz, E. M.; Guldberg, R. E. Synthetic scaffold coating with adeno-associated virus encoding BMP2 to promote endogenous bone repair. Cell Tissue Res. 2012, 347, 575-588.
93. Chen, Z.; Bozec, A.; Ramming, A.; Schett, G. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis. Nat Rev Rheumatol. 2019, 15, 9-17.
94. Lin, Y. J.; Anzaghe, M.; Schülke, S. Update on the pathomechanism, diagnosis, and treatment options for rheumatoid arthritis. Cells. 2020, 9, 880.
95. Bek, S.; Bojesen, A. B.; Nielsen, J. V.; Sode, J.; Bank, S.; Vogel, U.; Andersen, V. Systematic review and meta-analysis: pharmacogenetics of anti-TNF treatment response in rheumatoid arthritis. Pharmacogenomics J. 2017, 17, 403-411.
96. Watson Levings, R. S.; Smith, A. D.; Broome, T. A.; Rice, B. L.; Gibbs, E. P.; Myara, D. A.; Hyddmark, E. V.; Nasri, E.; Zarezadeh, A.; Levings, P. P.; Lu, Y.; White, M. E.; Dacanay, E. A.; Foremny, G. B.; Evans, C. H.; Morton, A. J.; Winter, M.; Dark, M. J.; Nickerson, D. M.; Colahan, P. T.; Ghivizzani, S. C. 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, 101-112.
97. Roseti, L.; Desando, G.; Cavallo, C.; Petretta, M.; Grigolo, B. Articular cartilage regeneration in osteoarthritis. Cells. 2019, 8, 1305.
98. Tao, K.; Frisch, J.; Rey-Rico, A.; Venkatesan, J. K.; Schmitt, G.; Madry, H.; Lin, J.; Cucchiarini, M. Co-overexpression of TGF-β and SOX9 via rAAV gene transfer modulates the metabolic and chondrogenic activities of human bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther. 2016, 7, 20.
99. Cucchiarini, M.; Madry, H. Biomaterial-guided delivery of gene vectors for targeted articular cartilage repair. Nat Rev Rheumatol. 2019, 15, 18-29.
100. Yang, R.; Chen, F.; Guo, J.; Zhou, D.; Luan, S. Recent advances in polymeric biomaterials-based gene delivery for cartilage repair. Bioact Mater. 2020, 5, 990-1003.
101. Rey-Rico, A.; Venkatesan, J. K.; Schmitt, G.; Concheiro, A.; Madry, H.; Alvarez-Lorenzo, C.; Cucchiarini, M. rAAV-mediated overexpression of TGF-β via vector delivery in polymeric micelles stimulates the biological and reparative activities of human articular chondrocytes in vitro and in a human osteochondral defect model. Int J Nanomedicine. 2017, 12, 6985-6996.
102. Rey-Rico, A.; Venkatesan, J. K.; Schmitt, G.; Speicher-Mentges, S.; Madry, H.; Cucchiarini, M. Effective remodeling of human osteoarthritic cartilage by SOX9 gene transfer and overexpression upon delivery of rAAV vectors in polymeric micelles. Mol Pharm. 2018, 15, 2816-2826.
103. Venkatesan, J. K.; Meng, W.; Rey-Rico, A.; Schmitt, G.; Speicher-Mentges, S.; Falentin-Daudré, C.; Leroux, A.; Madry, H.; Migonney, V.; Cucchiarini, M. Enhanced chondrogenic differentiation activities in human bone marrow aspirates via SOX9 overexpression mediated by pNaSS-grafted PCL film-guided rAAV gene transfer. Pharmaceutics. 2020, 12, 280.
104. Rybalko, V. Y.; Pham, C. B.; Hsieh, P. L.; Hammers, D. W.; Merscham-Banda, M.; Suggs, L. J.; Farrar, R. P. Controlled delivery of SDF-1α and IGF-1: CXCR4(+) cell recruitment and functional skeletal muscle recovery. Biomater Sci. 2015, 3, 1475-1486.
105. Blumenthal, B.; Golsong, P.; Poppe, A.; Heilmann, C.; Schlensak, C.; Beyersdorf, F.; Siepe, M. Polyurethane scaffolds seeded with genetically engineered skeletal myoblasts: a promising tool to regenerate myocardial function. Artif Organs. 2010, 34, E46-54.
106. Moimas, S.; Manasseri, B.; Cuccia, G.; Stagno d’Alcontres, F.; Geuna, S.; Pattarini, L.; Zentilin, L.; Giacca, M.; Colonna, M. R. AAV vector encoding human VEGF165-transduced pectineus muscular flaps increase the formation of new tissue through induction of angiogenesis in an in vivo chamber for tissue engineering: A technique to enhance tissue and vessels in microsurgically engineered tissue. J Tissue Eng. 2015, 6, 2041731415611717.
107. Wang, B.; Li, J.; Xiao, X. Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Proc Natl Acad Sci U S A. 2000, 97, 13714-13719.
108. Wang, B.; Li, J.; Fu, F. H.; Xiao, X. Systemic human minidystrophin gene transfer improves functions and life span of dystrophin and dystrophin/utrophin-deficient mice. J Orthop Res. 2009, 27, 421-426.
109. Tang, Y.; Reay, D. P.; Salay, M. N.; Mi, M. Y.; Clemens, P. R.; Guttridge, D. C.; Robbins, P. D.; Huard, J.; Wang, B. Inhibition of the IKK/NF-κB pathway by AAV gene transfer improves muscle regeneration in older mdx mice. Gene Ther. 2010, 17, 1476-1483.
110. Yang, Q.; Tang, Y.; Imbrogno, K.; Lu, A.; Proto, J. D.; Chen, A.; Guo, F.; Fu, F. H.; Huard, J.; Wang, B. AAV-based shRNA silencing of NF-κB ameliorates muscle pathologies in mdx mice. Gene Ther. 2012, 19, 1196-1204.
111. Yin, X.; Tang, Y.; Li, J.; Dzuricky, A. T.; Pu, C.; Fu, F.; Wang, B. Genetic ablation of P65 subunit of NF-κB in mdx mice to improve muscle physiological function. Muscle Nerve. 2017, 56, 759-767.
