Использование генной терапии на основе AAV-векторов в лечении офтальмологических заболеваний (обзор литературы)

Данная обзорная статья посвящена изучению текущего состояния генной терапии с использованием аденоассоциированных вирусов (AAV) в лечении офтальмологических заболеваний.

Цель исследования — оценить эффективность и безопасность применения генной терапии в лечении наследственных и приобретенных заболеваний глаз, а также обсудить последние достижения в этой области. Проведен систематический обзор научной литературы из баз данных MEDLINE, PubMed, Киберленинка, Mendeley, Web of Science и EMBASE. Для поиска использовались ключевые термины и их комбинации: «генная терапия», «аденоассоциированный вирус», «офтальмология», «наследственные заболевания глаз», «возрастная макулярная дегенерация», «глаукома», «клинические испытания». В обзор включены клинические исследования, экспертные статьи и метаанализы, фокусирующиеся на применении AAV в терапии глазных патологий.

Результаты. Исследования показывают, что генная терапия с использованием AAV представляет перспективное направление в лечении глазных заболеваний благодаря иммунной изоляции глаза и эффективности векторных систем. Однако вызванные AAV иммунные реакции остаются вызовом и требуют разработки специфических стратегий для их подавления. Подчеркивается значимость разработки менее иммуногенных капсидов и новых методов доставки векторов для повышения безопасности и эффективности терапии.

Заключение. Генная терапия с использованием AAV открывает новые возможности для лечения наследственных и приобретенных заболеваний глаз. Несмотря на существующие проблемы, связанные с иммунными реакциями, современные достижения в области разработки векторов и методов доставки генетического материала предвещают высокие перспективы для более безопасных и эффективных терапевтических подходов.

1. Ramlogan‑Steel CA, Murali A, Andrzejewski S, Dhungel B, Steel JC, Layton CJ. Gene therapy and the adeno‑associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations. Clin Exp Ophthalmol. 2019 May;47(4):521–536. doi: 10.1111/ceo.13416.

2. Егорова ТВ, Пискунов АА, Потеряев ДА. Генная терапия наследственных заболеваний на основе аденоассоциированных вирусных векторов: современные проблемы применения и пути их решения. БИОпрепараты. Профилактика, диагностика, лечение. 2024;24(2):123–139. doi: 10.30895/2221‑996X2024‑24‑2‑123‑139.

3. Guo D, Sun Y, Wu J, Ding L, Jiang Y, Xue Y, Ma Y, Sun F. Photoreceptor‑targeted extracellular vesicles‑mediated delivery of Cul7 siRNA for retinal degeneration therapy. Theranostics. 2024 Aug 12;14(13):4916–4932. doi: 10.7150/thno.99484.

4. McLaughlin T, Medina A, Perkins J, Yera M, Wang JJ, Zhang SX. Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications. Mol Neurodegener. 2022 Mar 28;17(1):25. doi: 10.1186/s13024‑022‑00528‑w.

5. Matsevich C, Gopalakrishnan P, Chang N, Obolensky A, Beryozkin A, Salameh M, Kostic C, Sharon D, Arsenijevic Y, Banin E. Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosa. Mol Ther. 2023 Oct 4;31(10):2948–2961. doi: 10.1016/j.ymthe.2023.08.011.

6. Jadhav V, Vaishnaw A, Fitzgerald K, Maier MA. RNA interference in the era of nucleic acid therapeutics. Nat Biotechnol. 2024 Mar;42(3):394–405. doi: 10.1038/s41587‑023‑02105‑y.

7. Duan D. Lethal immunotoxicity in high‑dose systemic AAV therapy. Mol Ther. 2023 Nov 1;31(11):3123–3126. doi: 10.1016/j.ymthe.2023.10.015. Epub 2023 Oct 10.

8. Mendell JR, Connolly AM, Lehman KJ, Griffin DA, Khan SZ, Dharia SD, QuintanaGallardo L, Rodino‑Klapac LR. Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations. Mol Ther Methods Clin Dev. 2022 Feb 26;25:74–83. doi: 10.1016/j.omtm.2022.02.011.

9. Li X, Wei X, Lin J, Ou L. A versatile toolkit for overcoming AAV immunity. Front Immunol. 2022 Sep 2;13:991832. doi: 10.3389/fimmu.2022.991832.

10. Tabebordbar M, Lagerborg KA, Stanton A, King EM, Ye S, Tellez L, Krunnfusz A, Tavakoli S, Widrick JJ, Messemer KA, Troiano EC, Moghadaszadeh B, Peacker BL, Leacock KA, Horwitz N, Beggs AH, Wagers AJ, Sabeti PC. Directed evolution of a family of AAV capsid variants enabling potent muscle‑directed gene delivery across species. Cell. 2021 Sep 16;184(19):4919–4938.e22. doi: 10.1016/j.cell.2021.08.028. Epub 2021 Sep 9.

11. Chacón‑Camacho ÓF, Astorga‑Carballo A, Zenteno JC. Terapia génica para enfermedades hereditarias oftalmológicas: avances y perspectivas [Gene therapy for hereditary ophthalmological diseases: Advances and future perspectives]. Gac Med Mex. 2015 Jul‑Aug;151(4):501–511. Spanish.

12. Mével M, Pichard V, Bouzelha M, Alvarez‑Dorta D, Lalys PA, Provost N, Allais M, Mendes A, Landagaray E, Ducloyer JB, Toublanc E, Galy A, Brument N, Lefevre GM, Gouin SG, Isiegas C, Le Meur G, Cronin T, Le Guiner C, Weber M, Moullier P, Ayuso E, Deniaud D, Adjali O. Mannose‑coupled AAV2: A second‑generation AAV vector for increased retinal gene therapy efficiency. Mol Ther Methods Clin Dev. 2024 Jan 17;32(1):101187. doi: 10.1016/j.omtm.2024.101187.

13. Weinmann J, Weis S, Sippel J, Tulalamba W, Remes A, El Andari J, Herrmann AK, Pham QH, Borowski C, Hille S, Schönberger T, Frey N, Lenter M, VandenDriessche T, Müller OJ, Chuah MK, Lamla T, Grimm D. Identification of a myotropic AAV by massively parallel in vivo evaluation of barcoded capsid variants. Nat Commun. 2020 Oct 28;11(1):5432. doi: 10.1038/s41467‑020‑19230‑w.

14. Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen‑Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR. Long‑term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015 May 14;372(20):1887– 1897. doi: 10.1056/NEJMoa1414221.

15. Bainbridge JWB, Mistry A, Schlichtenbrede FC, Smith A, Broderick C, De Alwis M, Georgiadis A, Taylor PM, Squires M, Sethi C, Charteris D, Thrasher AJ, Sargan D, Ali RR. Stable rAAV‑mediated transduction of rod and cone photoreceptors in the canine retina. Gene Therapy. 2003 Aug;10(16):1336–1344. doi: 10.1038/sj.gt.3301990

16. Le Meur G, Weber M, Péréon Y, Mendes‑Madeira A, Nivard D, Deschamps JY, Moullier P, Rolling F. Postsurgical assessment and long‑term safety of recombinant adeno‑associated virus‑mediated gene transfer into the retinas of dogs and primates. Arch Ophthalmol. 2005 Apr;123(4):500–506. doi: 10.1001/archopht.123.4.500.

17. Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z, Chen Y, Bote E, Grant RL, Golden JA, Narfstrom K, Syed NA, Orlin SE, High KA, Maguire AM, Bennett J. Safety and efficacy of subretinal readministration of a viral vector in large animals to treat congenital blindness. Sci Transl Med. 2010 Mar 3;2(21):21ra16. doi: 10.1126/scitranslmed.3000659.

18. Weber M, Rabinowitz J, Provost N, Conrath H, Folliot S, Briot D, Chérel Y, Chenuaud P, Samulski J, Moullier P, Rolling F. Recombinant adeno‑associated virus serotype 4 mediates unique and exclusive long‑term transduction of retinal pigmented epithelium in rat, dog, and nonhuman primate after subretinal delivery. Mol Ther. 2003 Jun;7(6):774–781. doi: 10.1016/s1525‑0016(03)00098‑4.

19. Seitz IP, Michalakis S, Wilhelm B, Reichel FF, Ochakovski GA, Zrenner E, Ueffing M, Biel M, Wissinger B, Bartz‑Schmidt KU, Peters T, Fischer MD; RD‑CURE Consortium. Superior Retinal Gene Transfer and Biodistribution Profile of Subretinal Versus Intravitreal Delivery of AAV8 in Nonhuman Primates. Invest Ophthalmol Vis Sci. 2017 Nov 1;58(13):5792–5801. doi: 10.1167/iovs.17‑22473.

20. Boyd RF, Boye SL, Conlon TJ, Erger KE, Sledge DG, Langohr IM, Hauswirth WW, Komáromy AM, Boye SE, Petersen‑Jones SM, Bartoe JT. Reduced retinal transduction and enhanced transgene‑directed immunogenicity with intravitreal delivery of rAAV following posterior vitrectomy in dogs. Gene Ther. 2016 Jun;23(6):548–556. doi: 10.1038/gt.2016.31.

21. Reichel FF, Dauletbekov DL, Klein R, Peters T, Ochakovski GA, Seitz IP, Wilhelm B, Ueffing M, Biel M, Wissinger B, Michalakis S, Bartz‑Schmidt KU, Fischer MD; RD‑CURE Consortium. AAV8 Can Induce Innate and Adaptive Immune Response in the Primate Eye. Mol Ther. 2017 Dec 6;25(12):2648–2660. doi: 10.1016/j.ymthe.2017.08.018.

22. Ye GJ, Komáromy AM, Zeiss C, Calcedo R, Harman CD, Koehl KL, Stewart GA, Iwabe S, Chiodo VA, Hauswirth WW, Aguirre GD, Chulay JD. Safety and Efficacy of AAV5 Vectors Expressing Human or Canine CNGB3 in CNGB3‑Mutant Dogs. Hum Gene Ther Clin Dev. 2017 Dec;28(4):197–207. doi: 10.1089/humc.2017.125.

23. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen‑Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231–2239. doi: 10.1056/NEJMoa0802268.

24. Gray SJ, Foti SB, Schwartz JW, Bachaboina L, Taylor‑Blake B, Coleman J, Ehlers MD, Zylka MJ, McCown TJ, Samulski RJ. Optimizing promoters for recombinant adenoassociated virus‑mediated gene expression in the peripheral and central nervous system using self‑complementary vectors. Hum Gene Ther. 2011 Sep;22(9):1143– 1153. doi: 10.1089/hum.2010.245.

25. Miraldi Utz V, Coussa RG, Antaki F, Traboulsi EI. Gene therapy for RPE65‑ related retinal disease. Ophthalmic Genet. 2018; 39: 671–677. DOI: 10.1080/13816810.2018.1533027.

26. Bouquet C, Vignal Clermont C, Galy A, Fitoussi S, Blouin L, Munk MR, Valero S, Meunier S, Katz B, Sahel JA, Thomasson N. Immune Response and Intraocular Inflammation in Patients With Leber Hereditary Optic Neuropathy Treated With Intravitreal Injection of Recombinant Adeno‑Associated Virus 2 Carrying the ND4 Gene: A Secondary Analysis of a Phase 1/2 Clinical Trial. JAMA Ophthalmol. 2019 Apr 1;137(4):399–406. doi: 10.1001/jamaophthalmol.2018.6902.

27. Maheshri N, Koerber JT, Kaspar BK, Schaffer DV. Directed evolution of adeno‑associated virus yields enhanced gene delivery vectors. Nat Biotechnol. 2006 Feb;24(2):198–204. doi: 10.1038/nbt1182.

28. Liu YF, Huang S, Ng TK, Liang JJ, Xu Y, Chen SL, Xu C, Zhang M, Pang CP, Cen LP. Longitudinal evaluation of immediate inflammatory responses after intravitreal AAV2 injection in rats by optical coherence tomography. Exp Eye Res. 2020 Apr;193:107955. doi: 10.1016/j.exer.2020.107955.

29. Tse LV, Klinc KA, Madigan VJ, Castellanos Rivera RM, Wells LF, Havlik LP, Smith JK, Agbandje‑McKenna M, Asokan A. Structure‑guided evolution of antigenically distinct adeno‑associated virus variants for immune evasion. Proc Natl Acad Sci USA. 2017 Jun 13;114(24):E4812–E4821. doi: 10.1073/pnas.1704766114. Epub 2017 May 30.

30. Vandenberghe LH, Wang L, Somanathan S, Zhi Y, Figueredo J, Calcedo R, Sanmiguel J, Desai RA, Chen CS, Johnston J, Grant RL, Gao G, Wilson JM. Heparin binding directs activation of T cells against adeno‑associated virus serotype 2 capsid. Nat Med. 2006 Aug;12(8):967–971. doi: 10.1038/nm1445.

31. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O’Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner‑Tschakarjan E, Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM. Adenovirus‑associated virus vector‑mediated gene transfer in hemophilia B. N Engl J Med. 2011 Dec 22;365(25):2357–2365. doi: 10.1056/NEJMoa1108046.

32. Cramer ML, Shao G, Rodino‑Klapac LR, Chicoine LG, Martin PT. Induction of Tcell infiltration and programmed death ligand 2 expression by adeno‑ associated virus in rhesus macaque skeletal muscle and modulation by prednisone. Hum. Gene Ther. 2017;28:493–509. DOI: 10.1089/hum.2016.113.

33. Unzu C, Herv´ as‑Stubbs S, Sampedro A, Maule´ on I, Manche˜ no U, Alfaro C, Serrano‑Mendioroz I, de Salamanca RE, Benito A, Fontanellas A. Transient and intensive pharmacological immunosuppression fails to improve AAV‑based liver gene transfer in non‑human primates. J. Transl. Med. 2012;10:122. DOI: 10.1186/14795876‑10‑122.

34. Mingozzi F, Anguela XM, Pavani G, Chen Y, Davidson RJ, Hui DJ, Yazicioglu M, Elkouby L, Hinderer CJ, Faella A, Howard C, Tai A, Podsakoff GM, Zhou S, BasnerTschakarjan E, Wright JF, High KA. Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med. 2013 Jul 17;5(194):194ra92. doi: 10.1126/scitranslmed.3005795.

35. Leborgne C, Barbon E, Alexander JM, Hanby H, Delignat S, Cohen DM, Collaud F, Muraleetharan S, Lupo D, Silverberg J, Huang K, van Wittengerghe L, Marolleau B, Miranda A, Fabiano A, Daventure V, Beck H, Anguela XM, Ronzitti G, Armour SM, Lacroix‑Desmazes S, Mingozzi F. IgG‑cleaving endopeptidase enables in vivo gene therapy in the presence of anti‑AAV neutralizing antibodies. Nat Med. 2020 Jul;26(7):1096–1101. doi: 10.1038/s41591‑020‑0911‑7.

36. Finn JD, Hui D, Downey HD, Dunn D, Pien GC, Mingozzi F, Zhou S, High KA. Proteasome inhibitors decrease AAV2 capsid derived peptide epitope presentation on MHC class I following transduction. Mol Ther. 2010 Jan;18(1):135–142. doi: 10.1038/mt.2009.257.

37. Al´e A, Bruna J, Navarro X, Udina E. Neurotoxicity induced by antineoplastic proteasome inhibitors. Neurotoxicology. 2014;43:28–35. DOI: 10.1016/j.neuro.2014.02.001.

38. Al´e A, Bruna J, Herrando M, Navarro X, Udina E. Toxic effects of bortezomib on primary sensory neurons and schwann cells of adult mice. Neurotox. Res. 2015;27:430–440. DOI: 10.1007/s12640‑014‑9514‑8.

39. Jacobson SG, Cideciyan AV, Roman AJ, Sumaroka A, Schwartz SB, Heon E, Hauswirth WW. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015 May 14;372(20):1920–1926. doi: 10.1056/NEJMoa1412965.

40. Li H, Lasaro MO, Jia B, Lin SW, Haut LH, High KA, Ertl HC. Capsid‑specific T‑cell responses to natural infections with adeno‑associated viruses in humans differ from those of nonhuman primates. Mol Ther. 2011 Nov;19(11):2021–2030. doi: 10.1038/mt.2011.81.