Current state and progress of rapamycin in the treatment of non-infectious uveitis_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Huan ,  Zhang Xiaomin

Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China;

Corresponding author：

Zhang Xiaomin, Email: xzhang08@.tmu.edu.cn

Keywords：

Sirolimus; Uveitis; Review

DOI：

10.3760/cma.j.cn511434-20200612-00280

Video：

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Glucocorticoids (GCS) are the main treatment for non-infectious uveitis (NIU). However, long-term GCS treatment may induce systemic side effects including hypertension, hyperlipidemia and diabetes. Patients may develop cataract, ocular hypertension or glaucoma because of topical application of GCS. Rapamycin (RAPA) exhibits immunosuppressive, antiangiogenic and antiproliferative effects. Animal experiments and clinical trials have shown that RAPA has therapeutic potential for NIU, especially the treatment of intravitreal injection. In particular, intravitreal injection of RAPA can result in minimal systemic exposure and reduce adverse events. Meanwhile, systemic unwanted effects should be concerned about. In recent years, some studies have attempted to employ nanostructured carriers to improve penetrating abilities of RAPA and efficacy of treatment for ocular posterior segment diseases. These carriers include micelles, liposomes, nanocrystals, polymeric nanoparticles, magnetic nanoparticles and so on. Whether they can load RAPA for treating NIU deserves further study and exploration.

Citation： Li Huan, Zhang Xiaomin. Current state and progress of rapamycin in the treatment of non-infectious uveitis. Chinese Journal of Ocular Fundus Diseases, 2021, 37(7): 558-562. doi: 10.3760/cma.j.cn511434-20200612-00280 Copy

1.	Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop[J]. Am J Ophthalmol, 2005, 140(3): 509-516. DOI: 10.1016/j.ajo.2005.03.057.
2.	Barry RJ, Nguyen QD, Lee RW, et al. Pharmacotherapy for uveitis: current management and emerging therapy[J]. Clin Ophthalmol, 2014, 8: 1891-1911. DOI: 10.2147/OPTH.S47778.
3.	Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel[J]. Am J Ophthalmol, 2000, 130(4): 492-513. DOI: 10.1016/s0002-9394(00)00659-0.
4.	Nguyen QD, Hatef E, Kayen B, et al. A cross-sectional study of the current treatment patterns in noninfectious uveitis among specialists in the United States[J]. Ophthalmology, 2011, 118(1): 184-190. DOI: 10.1016/j.ophtha.2010.03.029.
5.	Napoli KL, Taylor PJ. From beach to bedside: history of the development of sirolimus[J]. Therapeutic Drug Monit, 2001, 23(5): 559-586. DOI: 10.1097/00007691-200110000-00012.
6.	Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression[J]. Clin Biochem, 1998, 31(5): 335-340. DOI: 10.1016/s0009-9120(98)00045-9.
7.	Ohia EO, Mancino M, Kulkarni PS. Effects of steroids and immunosuppressive drugs on endotoxin-uveitis in rabbits[J]. J Ocul Pharmacol, 1992, 8(4): 295-307. DOI: 10.1089/jop.1992.8.295.
8.	Roberge FG, Xu D, Chan CC, et al. Treatment of autoimmune uveoretinitis in the rat with rapamycin, an inhibitor of lymphocyte growth factor signal transduction[J]. Curr Eye Res, 1993, 12(2): 197-203. DOI: 10.3109/02713689308999487.
9.	Nussenblatt RB, Rodrigues MM, Wacker WB, et al. Cyclosporin a. Inhibition of experimental autoimmune uveitis in lewis rats[J]. J Clin Invest, 1981, 67(4): 1228-1231. DOI: 10.1172/jci110138.
10.	Nussenblatt RB, Rodrigues MM, Salinas-Carmona MC, et al. Modulation of experimental autoimmune uveitis with cyclosporin A[J]. Arch Ophthalmol, 1982, 100(7): 1146-1149. DOI: 10.1001/archopht.1982.01030040124022.
11.	Zhang Z, Wu X, Duan J, et al. Low dose rapamycin exacerbates autoimmune experimental uveitis[J/OL]. PLoS One, 2012, 7(5): e36589[2012-05-04]. https://pubmed.ncbi.nlm.nih.gov/22574188/. DOI: 10.1371/journal.pone.0036589.
12.	Ikeda E, Hikita N, Eto K, et al. Tacrolimus-rapamycin combination therapy for experimental autoimmune uveoretinitis[J]. Jpn J Ophthalmol, 1997, 41(6): 396-402. DOI: 10.1016/s0021-5155(97)00083-x.
13.	Martin DF, DeBarge LR, Nussenblatt RB, et al. Synergistic effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis[J]. J Immunol, 1995, 154(2): 922-927.
14.	Roberge FG, Martin DF, Xu D, et al. Synergism between corticosteroids and rapamycin for the treatment of intraocular inflammation[J]. Ocul Immunol Inflamm, 1995, 3(3): 195-202. DOI: 10.3109/09273949509069112.
15.	Mudumba S, Bezwada P, Takanaga H, et al. Tolerability and pharmacokinetics of intravitreal sirolimus[J]. J Ocul Pharmacol Ther, 2012, 28(5): 507-514. DOI: 10.1089/jop.2011.0226.
16.	Manzano RP, Peyman GA, Khan P, et al. Testing intravitreal toxicity of rapamycin in rabbit eyes[J]. Arq Bras Oftalmol, 2009, 72(1): 18-22. DOI: 10.1590/s0004-27492009000100004.
17.	Douglas LC, Yi NY, Davis JL, et al. Ocular toxicity and distribution of subconjunctival and intravitreal rapamycin in horses[J]. J Vet Pharmacol Ther, 2008, 31(6): 511-516. DOI: 10.1111/j.1365-2885.2008.00986.x.
18.	Phillips BN, Wroblewski KJ. A retrospective review of oral low-dose sirolimus (rapamycin) for the treatment of active uveitis[J]. J Ophthalmic Inflamm Infect, 2010, 1(1): 29-34. DOI: 10.1007/s12348-010-0015-5.
19.	Sen HN, Larson TA, Meleth AD, et al. Subconjunctival sirolimus for the treatment of chronic active anterior uveitis: results of a pilot trial[J]. Am J Ophthalmol, 2012, 153(6): 1038-1042. DOI: 10.1016/j.ajo.2011.12.018.
20.	Dugel PU, Blumenkranz MS, Haller JA, et al. A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema[J]. Ophthalmology, 2012, 119(1): 124-131. DOI: 10.1016/j.ophtha.2011.07.034.
21.	Nguyen QD, Ibrahim MA, Watters A, et al. Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: primary 6-month results of the SAVE Study[J/OL]. J Ophthalmic Inflamm Infect, 2013, 3(1): 32[2013-02-11]. https://pubmed.ncbi.nlm.nih.gov/23514595/. DOI: 10.1186/1869-5760-3-32.
22.	Nguyen QD, Sadiq MA, Soliman MK, et al. The effect of different dosing schedules of intravitreal sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in the treatment of non-infectious uveitis (an American Ophthalmological Society thesis)[J/OL]. Trans Am Ophthalmol Soc, 2016, 114: T3[2016-08-11]. https://pubmed.ncbi.nlm.nih.gov/27630374/.
23.	Ibrahim MA, Sepah YJ, Watters A, et al. One-year outcomes of the SAVE study: sirolimus as a therapeutic approach for uveitis[J/OL]. Transl Vis Sci Technol, 2015, 4(2): 4[2015-03-10]. https://pubmed.ncbi.nlm.nih.gov/25774330/. DOI: 10.1167/tvst.4.2.4.
24.	Vigil EM, Sepah YJ, Watters AL, et al. Assessment of changes in quality of life among patients in the SAVE study-sirolimus as therapeutic approach to uveitis: a randomized study to assess the safety and bioactivity of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis[J/OL]. J Ophthalmic Inflamm Infect, 2015, 5: 13[2015-04-18]. https://pubmed.ncbi.nlm.nih.gov/25918559/. DOI: 10.1186/s12348-015-0044-1.
25.	Nguyen QD, Merrill PT, Clark WL, et al. Intravitreal sirolimus for noninfectious uveitis: a phase Ⅲ sirolimus study assessing double-masked uveitis treatment (SAKURA)[J]. Ophthalmology, 2016, 123(11): 2413-2423. DOI: 10.1016/j.ophtha.2016.07.029.
26.	Lescrauwaet B, Miserocchi E, Thurau S, et al. Association between visual function response and reduction of inflammation in noninfectious uveitis of the posterior segment[J]. Invest Ophthalmol Vis Sci, 2017, 58(9): 3555-3562. DOI: 10.1167/iovs.17-22049.
27.	Merrill PT, Clark WL, Banker AS, et al. Efficacy and safety of intravitreal sirolimus for noninfectious uveitis of the posterior segment: results from the sirolimus study assessing double-masked uveitis treatment (SAKURA) program[J]. Ophthalmology, 2020, 127(10): 1405-1415. DOI: 10.1016/j.ophtha.2020.03.033.
28.	Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial[J]. Ophthalmology, 2011, 118(10): 1916-1926. DOI: 10.1016/j.ophtha.2011.07.027.
29.	Lowder C, Belfort R Jr., Lightman S, et al , Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis[J]. Arch Ophthalmol, 2011, 129(5): 545-553. DOI: 10.1001/archophthalmol.2010.339.
30.	Zarranz-Ventura J, Carreño E, Johnston RL, et al. Multicenter study of intravitreal dexamethasone implant in noninfectious uveitis: indications, outcomes, and reinjection frequency[J]. Am J Ophthalmol, 2014, 158(6): 1136-1145.e5. DOI: 10.1016/j.ajo.2014.09.003.

1. Jabs DA, Nussenblatt RB, Rosenbaum JT, et al. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop[J]. Am J Ophthalmol, 2005, 140(3): 509-516. DOI: 10.1016/j.ajo.2005.03.057.
2. Barry RJ, Nguyen QD, Lee RW, et al. Pharmacotherapy for uveitis: current management and emerging therapy[J]. Clin Ophthalmol, 2014, 8: 1891-1911. DOI: 10.2147/OPTH.S47778.
3. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel[J]. Am J Ophthalmol, 2000, 130(4): 492-513. DOI: 10.1016/s0002-9394(00)00659-0.
4. Nguyen QD, Hatef E, Kayen B, et al. A cross-sectional study of the current treatment patterns in noninfectious uveitis among specialists in the United States[J]. Ophthalmology, 2011, 118(1): 184-190. DOI: 10.1016/j.ophtha.2010.03.029.
5. Napoli KL, Taylor PJ. From beach to bedside: history of the development of sirolimus[J]. Therapeutic Drug Monit, 2001, 23(5): 559-586. DOI: 10.1097/00007691-200110000-00012.
6. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression[J]. Clin Biochem, 1998, 31(5): 335-340. DOI: 10.1016/s0009-9120(98)00045-9.
7. Ohia EO, Mancino M, Kulkarni PS. Effects of steroids and immunosuppressive drugs on endotoxin-uveitis in rabbits[J]. J Ocul Pharmacol, 1992, 8(4): 295-307. DOI: 10.1089/jop.1992.8.295.
8. Roberge FG, Xu D, Chan CC, et al. Treatment of autoimmune uveoretinitis in the rat with rapamycin, an inhibitor of lymphocyte growth factor signal transduction[J]. Curr Eye Res, 1993, 12(2): 197-203. DOI: 10.3109/02713689308999487.
9. Nussenblatt RB, Rodrigues MM, Wacker WB, et al. Cyclosporin a. Inhibition of experimental autoimmune uveitis in lewis rats[J]. J Clin Invest, 1981, 67(4): 1228-1231. DOI: 10.1172/jci110138.
10. Nussenblatt RB, Rodrigues MM, Salinas-Carmona MC, et al. Modulation of experimental autoimmune uveitis with cyclosporin A[J]. Arch Ophthalmol, 1982, 100(7): 1146-1149. DOI: 10.1001/archopht.1982.01030040124022.
11. Zhang Z, Wu X, Duan J, et al. Low dose rapamycin exacerbates autoimmune experimental uveitis[J/OL]. PLoS One, 2012, 7(5): e36589[2012-05-04]. https://pubmed.ncbi.nlm.nih.gov/22574188/. DOI: 10.1371/journal.pone.0036589.
12. Ikeda E, Hikita N, Eto K, et al. Tacrolimus-rapamycin combination therapy for experimental autoimmune uveoretinitis[J]. Jpn J Ophthalmol, 1997, 41(6): 396-402. DOI: 10.1016/s0021-5155(97)00083-x.
13. Martin DF, DeBarge LR, Nussenblatt RB, et al. Synergistic effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis[J]. J Immunol, 1995, 154(2): 922-927.
14. Roberge FG, Martin DF, Xu D, et al. Synergism between corticosteroids and rapamycin for the treatment of intraocular inflammation[J]. Ocul Immunol Inflamm, 1995, 3(3): 195-202. DOI: 10.3109/09273949509069112.
15. Mudumba S, Bezwada P, Takanaga H, et al. Tolerability and pharmacokinetics of intravitreal sirolimus[J]. J Ocul Pharmacol Ther, 2012, 28(5): 507-514. DOI: 10.1089/jop.2011.0226.
16. Manzano RP, Peyman GA, Khan P, et al. Testing intravitreal toxicity of rapamycin in rabbit eyes[J]. Arq Bras Oftalmol, 2009, 72(1): 18-22. DOI: 10.1590/s0004-27492009000100004.
17. Douglas LC, Yi NY, Davis JL, et al. Ocular toxicity and distribution of subconjunctival and intravitreal rapamycin in horses[J]. J Vet Pharmacol Ther, 2008, 31(6): 511-516. DOI: 10.1111/j.1365-2885.2008.00986.x.
18. Phillips BN, Wroblewski KJ. A retrospective review of oral low-dose sirolimus (rapamycin) for the treatment of active uveitis[J]. J Ophthalmic Inflamm Infect, 2010, 1(1): 29-34. DOI: 10.1007/s12348-010-0015-5.
19. Sen HN, Larson TA, Meleth AD, et al. Subconjunctival sirolimus for the treatment of chronic active anterior uveitis: results of a pilot trial[J]. Am J Ophthalmol, 2012, 153(6): 1038-1042. DOI: 10.1016/j.ajo.2011.12.018.
20. Dugel PU, Blumenkranz MS, Haller JA, et al. A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema[J]. Ophthalmology, 2012, 119(1): 124-131. DOI: 10.1016/j.ophtha.2011.07.034.
21. Nguyen QD, Ibrahim MA, Watters A, et al. Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: primary 6-month results of the SAVE Study[J/OL]. J Ophthalmic Inflamm Infect, 2013, 3(1): 32[2013-02-11]. https://pubmed.ncbi.nlm.nih.gov/23514595/. DOI: 10.1186/1869-5760-3-32.
22. Nguyen QD, Sadiq MA, Soliman MK, et al. The effect of different dosing schedules of intravitreal sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in the treatment of non-infectious uveitis (an American Ophthalmological Society thesis)[J/OL]. Trans Am Ophthalmol Soc, 2016, 114: T3[2016-08-11]. https://pubmed.ncbi.nlm.nih.gov/27630374/.
23. Ibrahim MA, Sepah YJ, Watters A, et al. One-year outcomes of the SAVE study: sirolimus as a therapeutic approach for uveitis[J/OL]. Transl Vis Sci Technol, 2015, 4(2): 4[2015-03-10]. https://pubmed.ncbi.nlm.nih.gov/25774330/. DOI: 10.1167/tvst.4.2.4.
24. Vigil EM, Sepah YJ, Watters AL, et al. Assessment of changes in quality of life among patients in the SAVE study-sirolimus as therapeutic approach to uveitis: a randomized study to assess the safety and bioactivity of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis[J/OL]. J Ophthalmic Inflamm Infect, 2015, 5: 13[2015-04-18]. https://pubmed.ncbi.nlm.nih.gov/25918559/. DOI: 10.1186/s12348-015-0044-1.
25. Nguyen QD, Merrill PT, Clark WL, et al. Intravitreal sirolimus for noninfectious uveitis: a phase Ⅲ sirolimus study assessing double-masked uveitis treatment (SAKURA)[J]. Ophthalmology, 2016, 123(11): 2413-2423. DOI: 10.1016/j.ophtha.2016.07.029.
26. Lescrauwaet B, Miserocchi E, Thurau S, et al. Association between visual function response and reduction of inflammation in noninfectious uveitis of the posterior segment[J]. Invest Ophthalmol Vis Sci, 2017, 58(9): 3555-3562. DOI: 10.1167/iovs.17-22049.
27. Merrill PT, Clark WL, Banker AS, et al. Efficacy and safety of intravitreal sirolimus for noninfectious uveitis of the posterior segment: results from the sirolimus study assessing double-masked uveitis treatment (SAKURA) program[J]. Ophthalmology, 2020, 127(10): 1405-1415. DOI: 10.1016/j.ophtha.2020.03.033.
28. Multicenter Uveitis Steroid Treatment (MUST) Trial Research Group, Kempen JH, Altaweel MM, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial[J]. Ophthalmology, 2011, 118(10): 1916-1926. DOI: 10.1016/j.ophtha.2011.07.027.
29. Lowder C, Belfort R Jr., Lightman S, et al , Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis[J]. Arch Ophthalmol, 2011, 129(5): 545-553. DOI: 10.1001/archophthalmol.2010.339.
30. Zarranz-Ventura J, Carreño E, Johnston RL, et al. Multicenter study of intravitreal dexamethasone implant in noninfectious uveitis: indications, outcomes, and reinjection frequency[J]. Am J Ophthalmol, 2014, 158(6): 1136-1145.e5. DOI: 10.1016/j.ajo.2014.09.003.

Chinese Journal of Ocular Fundus Diseases

Current state and progress of rapamycin in the treatment of non-infectious uveitis

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