Pay attention to the detection and treatment of ocular gene therapy viral vector-associated immunity_Chinese Journal of Ocular Fundus Diseases

Authors：

 Sun Xiaodong , Chen Jieqiong

Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, National Clinical Research Center for Eye Diseases, Shanghai Key Laboratory of Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai 200080, China;

Corresponding author：

Sun Xiaodong, Email: xdsun@sjtu.edu.cn

Keywords：

Gene therapy; Inflammation; Vector-associated immunity; Editorial

DOI：

10.3760/cma.j.cn511434-20220629-00389

Video：

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Abstract Full text Figures/Tables Video References Cited by

The application of gene therapy in ocular diseases is gradually expanding from mono-gene inherited diseases to multigene, multifactorial, common and chronic diseases. This emerging therapeutic approach is still in the early exploratory stage of treating diseases, and the expected benefits and risks remain highly uncertain. In the delivery process of gene therapy drugs, viral vector is currently one of the most mature and widely used vectors. The occurrence of vector-associated immunity will affect the short-term and long-term effects of gene therapy, and even cause permanent and serious damage to visual function. Therefore, gene therapy vector-associated immunity is the focus and challenge for the safety and long-term efficacy of gene therapy. During the perioperative and follow-up of gene therapy, attention should be paid to the monitoring of vector-associated immune inflammation, and appropriate measures should be taken to deal with the corresponding immune response, so as to achieve the best visual benefits for patients.

Citation： Sun Xiaodong, Chen Jieqiong. Pay attention to the detection and treatment of ocular gene therapy viral vector-associated immunity. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 621-625. doi: 10.3760/cma.j.cn511434-20220629-00389 Copy

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1. Constable IJ, Pierce CM, Lai CM, et al. Phase 2a randomized clinical trial: safety and post hoc analysis of subretinal rAAV. sFLT-1for wet age-related macular degeneration[J]. EBioMedicine, 2016, 14: 168-175. DOI: 10.1016/j.ebiom.2016.11.016.
2. Yin D, Ling S, Wang D, et al. Targeting herpes simplex virus with CRISPR-Cas9 cures herpetic stromal keratitis in mice[J]. Nat Biotechnol, 2021, 39(5): 567-577. DOI: 10.1038/s41587-020-00781-8.
3. 沈科炯, 沈吟. 遗传性视网膜疾病腺相关病毒载体基因治疗新进展[J]. 中华眼底病杂志, 2020, 36(3): 242-248. DOI: 10.3760/cma.j.cn511434-20190705-00214.Shen KJ, Shen Y. New advances in gene therapy with adenoviral vectors for inherited retinal diseases[J]. Chin J Ocul Fundus Dis, 2020, 36(3): 242-248. DOI: 10.3760/cma.j.cn511434-20190705-00214.
4. Timmers AM, Newmark JA, Turunen HT, et al. Ocular inflammatory response to intravitreal injection of adeno-associated virus vector: relative contribution of genome and capsid[J]. Hum Gene Ther, 2020, 31(1-2): 80-89. DOI: 10.1089/hum.2019.144.
5. Bainbridge JWB, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis[J]. N Engl J Med, 2015, 372(20): 1887-1897. DOI: 10.1056/NEJMoa1414221.
6. Sauter MM, Kolb AW, Brandt CR. Toll-like receptors 4, 5, 6 and 7 are constitutively expressed in non-human primate retinal neurons[J]. J Neuroimmunol, 2018, 322: 26-35. DOI: 10.1016/j.jneuroim.2018.06.007.
7. Chandler LC, Barnard AR, Caddy SL, et al. Enhancement of adeno-associated virus-mediated gene therapy using hydroxychloroquine in murine and human tissues[J]. Mol Ther Methods Clin Dev, 2019, 14: 77-89. DOI: 10.1016/j.omtm.2019.05.012.
8. Liu YF, Huang S, Ng TK, et al. Longitudinal evaluation of immediate inflammatory responses after intravitreal AAV2 injection in rats by optical coherence tomography[J/OL]. Exp Eye Res, 2020, 193: 107955[2020-02-01]. https://pubmed.ncbi.nlm.nih.gov/32017940/. DOI: 10.1016/j.exer.2020.107955.
9. Boutin S, Monteilhet V, Veron P, et al. Prevalence of serum lgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors[J]. Hum Gene Ther, 2010, 21(6): 704-712. DOI: 10.1089/hum.2009.182.
10. Ronzitti G, Gross DA, Mingozzi F. Human immune responses to adeno-associated virus (AAV) vectors[J]. Front Immunol, 2020, 11: 670. DOI: 10.3389/fimmu.2020.00670.
11. Greenberg B, Butler J, Felker GM, et al. Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure[J]. Gene Ther, 2016, 23(3): 313-319. DOI: 10.1038/gt.2015.109.
12. Lee JH, Wang JH, Chen J, et al. Gene therapy for visual loss: opportunities and concerns[J]. Prog Retin Eye Res, 2019, 68: 31-53. DOI: 10.1016/j.preteyeres.2018.08.003.
13. Kumar SRP, Hoffman BE, Terhorst C, et al. The balance between CD8+ T cell-mediated clearance of AAV-encoded antigen in the liver and tolerance is dependent on the vector dose[J]. Mol Ther, 2017, 25(4): 880-891. DOI: 10.1016/j.ymthe.2017.02.014.
14. Cukras C, Wiley HE, Jeffrey BG, et al. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase Ⅰ/Ⅱa trial by intravitreal delivery[J]. Mol Ther, 2018, 26(9): 2282-2294. DOI: 10.1016/j.ymthe.2018.05.025.
15. Gange WS, Sisk RA, Besirli CG, et al. Perifoveal chorioretinal atrophy after subretinal voretigene neparvovec-rzyl for RPE65-mediated Leber congenital amaurosis[J]. Ophthalmol Retina, 2022, 6(1): 58-64. DOI: 10.1016/j.oret.2021.03.016.
16. Sodi A, Banfi S, Testa F, et al. RPE65-associated inherited retinal diseases: consensus recommendations for eligibility to gene therapy[J]. Orphanet J Rare Dis, 2021, 16(1): 257. DOI: 10.1186/s13023-021-01868-4.
17. Williams A, Flavell RA, Eisenbarth SC. The role of NOD-like receptors in shaping adaptive immunity[J]. Curr Opin Immunol, 2010, 22(1): 34-40. DOI: 10.1016/j.coi.2010.01.004.
18. 韩如意, 金子兵. 遗传性眼底病基因和干细胞治疗趋势与面临的挑战和机遇[J]. 中华眼底病杂志, 2018, 34(6): 519-525. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.001.Han RY, Jin ZB. Progress and opportunities of gene and stem cell therapy on hereditary ocular fundus diseases[J]. Chin J Ocul Fundus Dis, 2018, 34(6): 519-525. DOI: 10.3760/cma.j.issn.1005-1015.2018.06.001.
19. Li W, Asokan A, Wu Z, et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles[J]. Mol Ther, 2008, 16(7): 1252-1260. DOI: 10.1038/mt.2008.100.
20. Seitz IP, Michalakis S, Wilhelm B, et al. Superior retinal gene transfer and biodistribution profile of subretinal versus intravitreal delivery of AAV8 in nonhuman primates[J]. Invest Ophthalmol Vis Sci, 2017, 58(13): 5792-5801. DOI: 10.1167/iovs.17-22473.
21. Pavlou M, Schön C, Occelli LM, et al. Novel AAV capsids for intravitreal gene therapy of photoreceptor disorders[J/OL]. EMBO Mol Med, 2021, 13(4): e13392[2021-04-09]. https://pubmed.ncbi.nlm.nih.gov/33616280/. DOI: 10.15252/emmm.202013392.
22. Ding K, Shen J, Hafiz Z, et al. AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expression[J]. J Clin Invest, 2019, 129(11): 4901-4911. DOI: 10.1172/JCI129085.
23. Yeh S, Khurana RN, Shah M, et al. Efficacy and safety of suprachoroidal CLS-TA for macular edema secondary to noninfectious uveitis: phase 3 randomized trial[J]. Ophthalmology, 2020, 127(7): 948-955. DOI: 10.1016/j.ophtha.2020.01.006.
24. 杨培增. 关注我国葡萄膜炎的病因和类型的变化[J]. 中华眼科杂志, 2008, 44(10): 865-866. DOI: 10.3321/j.issn:0412-4081.2008.10.001.Yang PZ. Concern on the changes of clinical pattern and etiological factors in uveitis in China[J]. Chin J Ophthalmol, 2008, 44(10): 865-866. DOI: 10.3321/j.issn:0412-4081.2008.10.001.
25. Shen J, Kim J, Tzeng SY, et al. Suprachoroidal gene transfer with nonviral nanoparticles[J/OL]. Sci Adv, 2020, 6(27): eaba1606[2020-07-03]. https://pubmed.ncbi.nlm.nih.gov/32937452/. DOI: 10.1126/sciadv.aba1606.

Chinese Journal of Ocular Fundus Diseases

Pay attention to the detection and treatment of ocular gene therapy viral vector-associated immunity

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