Efficacy of RCI001 As a Therapeutic Candidate in a Primary Sjögren Syndrome Mouse Model

Overview

Journal Cornea

Specialty Ophthalmology

Date 2024 Sep 17

PMID 39288434

Authors

Hyereen Kang

Young-Ho Jung

Jayoon Moon

Jin Suk Ryu

Chang Ho Yoon

Yong Ho Kim

Mee Kum Kim

Dong Hyun Kim

Affiliations

Soon will be listed here.

Abstract

Purpose: The aim of this study was to investigate the efficacy of RCI001 (RCI) in a mouse model of primary Sjögren syndrome.

Methods: Eight 12-week-old NOD.B10-H2b mice were used in this study. All experimental animals were randomly divided into phosphate-buffered saline (PBS) and RCI groups in NOD.B10-H2b mice. The eyes of mice were topically treated with PBS or RCI twice a day for a week. Ocular surface staining (OSS) and tear secretion were compared between before and after treatment. The transcript levels of inflammatory cytokines and nicotinamide adenine dinucleotide phosphate oxidase (NOX) in the conjunctiva and cornea (CC) and lacrimal gland were assayed. In addition, immunofluorescence staining of the conjunctiva was assessed.

Results: The RCI group showed significant clinical improvement in OSS and tear secretion after 1 week of treatment compared with the baseline (both P < 0.001) and showed better improvement in OSS and tear secretion than the PBS group after 1 week of treatment (both P < 0.05). The levels of IL-1β and IL-17 in CC and IL-6 in the lacrimal gland were also significantly reduced in the RCI group compared with the PBS group (each P < 0.05). Transcript levels of NOX2 and NOX4 were also significantly reduced in CC of the RCI group compared with those of the PBS group ( P < 0.05). The RCI group also resulted in lower conjunctival expression of oxidative stress markers (4-hydroxy-2-nonenal, hexanoyl-lysine, and NOX4) than the PBS group.

Conclusions: Topical RCI001 demonstrated excellent therapeutic efficacy in a mouse model of primary Sjögren syndrome by inhibiting inflammation and oxidative stress.

References

Chung H, Ha Y, Kim Y, Kim D, Shin D . Ocular Distribution and Pharmacokinetics of 8-Oxo-2'-Deoxyguanosine: A Novel Therapeutic Candidate of Ocular Surface Diseases. J Ocul Pharmacol Ther. 2022; 38(8):561-566. DOI: 10.1089/jop.2022.0054. View

Hordijk P . Regulation of NADPH oxidases: the role of Rac proteins. Circ Res. 2006; 98(4):453-62. DOI: 10.1161/01.RES.0000204727.46710.5e. View

Chacko B, Wall S, Kramer P, Ravi S, Mitchell T, Johnson M . Pleiotropic effects of 4-hydroxynonenal on oxidative burst and phagocytosis in neutrophils. Redox Biol. 2016; 9:57-66. PMC: 4939321. DOI: 10.1016/j.redox.2016.06.003. View

Kim D, Im S, Yoon J, Kim S, Kim M, Chung M . Comparison of therapeutic effects between topical 8-oxo-2'-deoxyguanosine and corticosteroid in ocular alkali burn model. Sci Rep. 2021; 11(1):6909. PMC: 7994716. DOI: 10.1038/s41598-021-86440-7. View

Pflugfelder S, de Paiva C, Villarreal A, Stern M . Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factor-beta2 production. Cornea. 2008; 27(1):64-9. DOI: 10.1097/ICO.0b013e318158f6dc. View

Sheppard J, Nichols K . Dry Eye Disease Associated with Meibomian Gland Dysfunction: Focus on Tear Film Characteristics and the Therapeutic Landscape. Ophthalmol Ther. 2023; 12(3):1397-1418. PMC: 10164226. DOI: 10.1007/s40123-023-00669-1. View

Tishler M, Yaron I, Geyer O, Shirazi I, Naftaliev E, Yaron M . Elevated tear interleukin-6 levels in patients with Sjögren syndrome. Ophthalmology. 1998; 105(12):2327-9. DOI: 10.1016/S0161-6420(98)91236-2. View

Song M, Ku Y, Kim S, Chung M, Kim Y, Kim D . Comparison of Corneal Epithelial Wound Healing between Topical RCI001, Solcoseryl, and Polydeoxyribonucleotide in the Murine Ocular Alkali Burn Model. Korean J Ophthalmol. 2023; 37(3):236-244. PMC: 10270771. DOI: 10.3341/kjo.2023.0019. View

Kim D, Cho I, Kim H, Jung J, Kim J, Lee K . Anti-inflammatory effects of 8-hydroxydeoxyguanosine in LPS-induced microglia activation: suppression of STAT3-mediated intercellular adhesion molecule-1 expression. Exp Mol Med. 2006; 38(4):417-27. DOI: 10.1038/emm.2006.49. View

10.

Vivino F . Sjogren's syndrome: Clinical aspects. Clin Immunol. 2017; 182:48-54. DOI: 10.1016/j.clim.2017.04.005. View

11.

Qin B, Wang J, Yang Z, Yang M, Ma N, Huang F . Epidemiology of primary Sjögren's syndrome: a systematic review and meta-analysis. Ann Rheum Dis. 2014; 74(11):1983-9. DOI: 10.1136/annrheumdis-2014-205375. View

12.

Wu K, Chen W, Chu-Bedard Y, Patel G, Tran S . Management of Sjogren's Dry Eye Disease-Advances in Ocular Drug Delivery Offering a New Hope. Pharmaceutics. 2023; 15(1). PMC: 9861012. DOI: 10.3390/pharmaceutics15010147. View

13.

Ogawa Y, Shimizu E, Tsubota K . Interferons and Dry Eye in Sjögren's Syndrome. Int J Mol Sci. 2018; 19(11). PMC: 6274689. DOI: 10.3390/ijms19113548. View

14.

Ibanez-Cabellos J, Pallardo F, Garcia-Gimenez J, Seco-Cervera M . Oxidative Stress and Epigenetics: miRNA Involvement in Rare Autoimmune Diseases. Antioxidants (Basel). 2023; 12(4). PMC: 10135388. DOI: 10.3390/antiox12040800. View

15.

Perez V, Stern M, Pflugfelder S . Inflammatory basis for dry eye disease flares. Exp Eye Res. 2020; 201:108294. PMC: 7736538. DOI: 10.1016/j.exer.2020.108294. View

16.

de Paiva C, Hwang C, Pitcher 3rd J, Pangelinan S, Rahimy E, Chen W . Age-related T-cell cytokine profile parallels corneal disease severity in Sjogren's syndrome-like keratoconjunctivitis sicca in CD25KO mice. Rheumatology (Oxford). 2009; 49(2):246-58. PMC: 2909796. DOI: 10.1093/rheumatology/kep357. View

17.

Bang S, Yeon C, Adhikari N, Neupane S, Kim H, Lee D . Cyclosporine A eyedrops with self-nanoemulsifying drug delivery systems have improved physicochemical properties and efficacy against dry eye disease in a murine dry eye model. PLoS One. 2019; 14(11):e0224805. PMC: 6860930. DOI: 10.1371/journal.pone.0224805. View

18.

Ago T, Kuroda J, Kamouchi M, Sadoshima J, Kitazono T . Pathophysiological roles of NADPH oxidase/nox family proteins in the vascular system. -Review and perspective-. Circ J. 2011; 75(8):1791-800. DOI: 10.1253/circj.cj-11-0388. View

19.

Choi S, Choi H, Lee S, Ko S, You H, Ye S . Anti-inflammatory effects of 8-hydroxy-2'-deoxyguanosine on lipopolysaccharide-induced inflammation via Rac suppression in Balb/c mice. Free Radic Biol Med. 2007; 43(12):1594-603. DOI: 10.1016/j.freeradbiomed.2007.08.022. View

20.

Im S, Kim H, Yoon J, Oh J, Kim M, Chung M . Therapeutic Effects of Topical 8-Oxo-2'-deoxyguanosine on Ethanol-Induced Ocular Chemical Injury Models. Cornea. 2018; 37(10):1311-1317. DOI: 10.1097/ICO.0000000000001671. View