Gene therapy: New and future treatments for uveitis

Abstract

Uveitis, characterized by intraocular inflammation, has significant management challenges due to its diverse etiologies and complicated pathophysiology. The current first-line treatments primarily aim to calm inflammation with the underlying causes unaffected, often associated with systemic side effects, limited long-term efficacy, and disease recurrence. Gene therapies, as powerful therapeutic approaches, have been applied to treat various genetic and non-genetic diseases. However, the development of gene therapy for uveitis has been investigated less. This review discusses the possible targets and therapeutic approaches for uveitis gene therapy by analyzing some research examples in exogenous gene expression, RNAi, antisense therapy, and the CRISPR gene editing system. Furthermore, we discuss the limitations of listed gene therapies for uveitis and propose future research directions and potential strategies to overcome current challenges.

Keywords

ASO / CRISPR / gene therapy / RNAi (siRNA) / uveitis

References

[1] Miserocchi E , Fogliato G , Modorati G , Bandello F . Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol. 2013; 23 (5): 705- 717.

[2] Tan H , Feng X , Yang P . Association between uveitis onset and economic development in Chinese mainland. BMC Publ Health. 2023; 23 (1): 1711.

[3] Agrawal R , Thng ZX , Gupta A , et al. Infectious uveitis: conversations with the experts. Ocul Immunol Inflamm. 2023; 31 (7): 1333- 1341.

[4] Wu X , Tao M , Zhu L , Zhang T , Zhang M . Pathogenesis and current therapies for non-infectious uveitis. Clin Exp Med. 2023; 23 (4): 1089- 1106.

[5] Ghoraba HH , Akhavanrezayat A , Karaca I , et al. Ocular gene therapy: a literature review with special focus on immune and inflammatory responses. Clin Ophthalmol. 2022; 16: 1753- 1771.

[6] Kulkarni JA , Witzigmann D , Thomson SB , et al. The current landscape of nucleic acid therapeutics. Nat Nanotechnol. 2021; 16 (6): 630- 643.

[7] Roehr B . Fomivirsen approved for CMV retinitis. J Int Assoc Phys AIDS Care. 1998; 4: 14- 16.

[8] Keefe AD , Pai S , Ellington A . Aptamers as therapeutics. Nat Rev Drug Discov. 2010; 9 (7): 537- 550.

[9] Choi EH , Suh S , Sears AE , et al. Genome editing in the treatment of ocular diseases. Exp Mol Med. 2023; 55 (8): 1678- 1690.

[10] Buggage RR , Bordet T . Gene therapy for uveitis. Int Ophthalmol Clin. 2021; 61 (4): 249- 270.

[11] You C , Sahawneh HF , Ma L , Kubaisi B , Schmidt A , Foster CS . A review and update on orphan drugs for the treatment of noninfectious uveitis. Clin Ophthalmol. 2017; 11: 257- 265.

[12] Pineda-Sierra JS , Cifuentes-González C , Rojas-Carabali W , Muñoz-Vargas PT , Henao-Posada A , de-la-Torre A . Clinical characterization of patients with HLA-B27-associated uveitis and evaluation of the impact of systemic treatment on the recurrence rate: a crosssectional study. J Ophthalmic Inflamm Infect. 2023; 13 (1): 38.

[13] Liu J , Liao X , Li N , et al. Single-cell RNA sequencing reveals inflammatory retinal microglia in experimental autoimmune uveitis. MedComm. 2024; 5 (4).

[14] Hou S , Du L , Lei B , et al. Genome-wide association analysis of Vogt-Koyanagi-Harada syndrome identifies two new susceptibility loci at 1p31.2 and 10q21.3. Nat Genet. 2014; 46 (9): 1007- 1011.

[15] Huang X-F , Li Z , De Guzman E , et al. Genomewide association study of acute anterior uveitis identifies new susceptibility loci. Invest Ophthalmol Vis Sci. 2020; 61 (6): 3.

[16] O'Rourke M , Fearon U , Sweeney CM , et al. The pathogenic role of dendritic cells in non-infectious anterior uveitis. Exp Eye Res. 2018; 173: 121- 128.

[17] Leal I , Rodrigues FB , Sousa DC , et al. Efficacy and safety of intravitreal anti-tumour necrosis factor drugs in adults with noninfectious uveitis—a systematic review. Acta Ophthalmol. 2018; 96 (6): e665- e675.

[18] Touchard E , Benard R , Bigot K , et al. Non-viral ocular gene therapy, pEYS606, for the treatment of non-infectious uveitis: preclinical evaluation of the medicinal product. J Contr Release. 2018; 285: 244- 251.

[19] Zhang C , Delawary M , Huang P , Korchak JA , Suda K , Zubair AC . IL-10 mRNA engineered MSCs demonstrate enhanced antiinflammation in an acute GvHD model. Cells. 2021; 10 (11): 3101.

[20] Tian L , Yang P , Lei B , et al. AAV2-Mediated subretinal gene transfer of hIFN-α attenuates experimental autoimmune uveoretinitis in mice. PLoS One. 2011; 6 (5): e19542.

[21] Crabtree E , Uribe K , Smith SM , et al. Inhibition of experimental autoimmune uveitis by intravitreal AAV-Equine-IL10 gene therapy. PLoS One. 2022; 17 (8): e0270972.

[22] Chen S , Yan H , Sun B , Zuo A , Liang D . Subretinal transfection of chitosan-loaded TLR3-siRNA for the treatment of experimental autoimmune uveitis. Eur J Pharm Biopharm. 2013; 85 (3): 726- 735.

[23] Hou Y , Xing L , Fu S , et al. Down-regulation of inducible co-stimulator(ICOS) by intravitreal injection of small interfering RNA (siRNA) plasmid suppresses ongoing experimental autoimmune uveoretinitis in rats. Graefes Arch Clin Exp Ophthalmol. 2009; 247 (6): 755- 765.

[24] Iwata D , Kitamura M , Kitaichi N , et al. Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA. Exp Eye Res. 2010; 90 (1): 41- 48.

[25] Gupta A , Kafetzis KN , Tagalakis AD , Wai Y , Man C . RNA therapeutics in ophthalmology - translation to clinical trials. Exp Eye Res. 2021; 205: 108482.

[26] Pierce EA , Aleman TS , Ashimatey B , et al. Safety and efficacy of EDIT-101 for treatment of CEP290-associated retinal degeneration. Invest Ophthalmol Vis Sci. 2023; 64: 3785.

[27] Bigini F , Lee SH , Sun YJ , Sun Y , Mahajan VB . Unleashing the potential of CRISPR multiplexing: harnessing Cas12 and Cas13 for precise gene modulation in eye diseases. Vis Res. 2023; 213: 108317.

[28] Broughton JP , Deng X , Yu G , et al. CRISPR-Cas12-based detection of SARS-CoV-2. Nat Biotechnol. 2020; 38 (7): 870- 874.

[29] Velez G , Roybal CN , Colgan D , Tsang SH , Bassuk AG , Mahajan VB . Precision medicine: personalized proteomics for the diagnosis and treatment of idiopathic inflammatory disease. JAMA Ophthalmol. 2016; 134 (4): 444- 448.

[30] Sepah YJ , Velez G , Tang PH , et al. Proteomic analysis of intermediate uveitis suggests myeloid cell recruitment and implicates IL-23 as a therapeutic target. Am J Ophthalmol Case Rep. 2020; 18: 100646.

[31] Guo LY , Bian J , Davis AE , et al. Multiplexed genome regulation in vivo with hyper-efficient Cas12a. Nat Cell Biol. 2022; 24 (4): 590- 600.

[32] Li X , Wang G , Wang X , et al. OR11H1 missense variant confers the susceptibility to vogt-koyanagi-harada disease by mediating Gadd45g expression. Adv Sci. 2024; 11.

[33] Liu X , Meng J , Liao X , et al. A de novo missense mutation in MPP2 confers an increased risk of Vogt-Koyanagi-Harada disease as shown by trio-based whole-exome sequencing. Cell Mol Immunol. 2023; 20 (11): 1379- 1392.

[34] Bulcha JT , Wang Y , Ma H , Tai PWL , Gao G . Viral vector platforms within the gene therapy landscape. Signal Transduct Targeted Ther. 2021; 6 (1): 53.

[35] Wang C , Pan C , Yong H , et al. Emerging non-viral vectors for gene delivery. J Nanobiotechnol. 2023; 21 (1): 272.

[36] Chen H , Liu D , Guo J , et al. Branched chemically modified poly tails enhance the translation capacity of mRNA. Nat Biotechnol. 2024.

[37] Chen Q , Zhang Y , Yin H . Recent advances in chemical modifications of guide RNA, mRNA and donor template for CRISPR-mediated genome editing. Adv Drug Deliv Rev. 2021; 168: 246- 258.

[38] Karikó K , Muramatsu H , Welsh FA , et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008; 16 (11): 1833- 1840.

[39] Gao S , Guan H , Bloomer H , et al. Harnessing non-Watson-Crick's base pairing to enhance CRISPR effectors cleavage activities and enable gene editing in mammalian cells. Proc Natl Acad Sci USA. 2024; 121 (2): e2308415120.

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The Author(s). Eye & ENT Research published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.