Will JNK Inhibitors Play Key Roles in Ocular Disease Treatments?

Will JNK Inhibitors Play Key Roles in Ocular Disease Treatments?

November 24, 2021

C−Jun N−terminal kinases (JNKs) are a family of protein kinases (mitogen activated  protein (MAP) kinases) that play a key role in stress signaling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death, and regulation of cellular senescence (proliferation, apoptosis, survival, tumorigenesis, and tissue morphogenesis.)

Jnk1 (MAPK8), jnk2 (MAPK9), and Jnk3 (MAPK10), encode for 10 different splice variants with molecular weights of 46, 55, and 57 kDa. JNK1 and JNK2 have a broad tissue distribution whereas JNK3 is mainly localized in neurons (brain) and lesser in the heart and the testis.

Recent preclinical and clinical studies indicate a potential role of JNK inhibitors in inflammatory conditions such as IBD (Inflammatory Bowel Disease), Sudden Hearing Loss, Viral infections, Dermatology and Ophthalmology. 

In Ophthalmology, several companies have been conducting preclinical and clinical studies in Aged Macular Degenerations (AMD) and Diabetic Retinopathy/Diabetic Edema. Current data indicate that inflammation plays an important role in both dry and wet AMD including mild infiltration of polymorphonuclear leukocytes, macrophages, and accumulation of microglia as well as the presence of inflammatory mediators such as the complement pathway, cytokines, and chemokines.

JNKs may interfere with insulin action in the retina and are activated by inflammatory cytokines and free fatty acids, molecules that have been implicated in the development of type 2 diabetes. Scientists keep searching if JNKs have clinical advantage over Anti-VEGF treatment, which is associated with complications such as:

·      Increased risk of geographic atrophy

·      Requires frequent injections (increased risk of complication rate)

·      Only reduces VEGF levels no other effect on inflammation

·      Increased risk of CV adverse events (myocardial infarction, stroke...)

·      Reduces choriocapillaris thickness and causes optic nerve atrophy

·    Long−term benefits are controversial (while reducing Diabetic Macular Edema, they also reducing choriocapillaris thickness which likely brings patients’ vision back to pre−treatment level)

Ocular inflammation in Post-Surgery, Uveitis and even in Dry Eye diseases are other key ophthalmic diseases where JNK inhibitory compounds are being tested. Clinical stage biopharma company, Kuste Biopharma has been searching on peptide based / JNK compounds. Their compound’s preclinical data suggests promising effects to treat eye conditions in which there is an inflammatory component.

It enters intracellularly and provides local therapeutic anti-inflammatory effect without systemic exposure and associated toxicity. It also demonstrated a good safety and tolerability profile when administered as a single dose by the subconjunctival route.

Even though all are in early stages, those preclinical and clinical studies are giving the industry a great motivation to invest in JNK further.

Useful references:

1. Christophe Chiquet et al. Postoperative Ocular Inflammation: A Single Subconjunctival Injection of XG-102 Compared to Dexamethasone Drops in a Randomized Trial

2. Li, De-Quan, et al. "JNK and ERK MAP kinases mediate induction of IL-1β, TNF-α and IL-8 following hyperosmolar stress in human limbal epithelial cells." Experimental eye research 82.4 (2006): 588-596.

3. Kyosseva, Svetlana V. "Targeting MAPK signaling in age-related macular degeneration." Ophthalmology and eye diseases 8 (2016): OED-S32200.

4. Beydoun, Talal, et al. "Subconjunctival injection of XG-102, a JNK inhibitor peptide, in patients with intraocular inflammation: a safety and tolerability study." Journal of Ocular Pharmacology and Therapeutics 31.2 (2015): 93-99.

5. Chan, Chi-Ming, et al. "Reactive oxygen species-dependent mitochondrial dynamics and autophagy confer protective effects in retinal pigment epithelial cells against sodium iodate-induced cell death." Journal of biomedical science 26.1 (2019): 1-11.

6. Jin, Xiaolu, et al. "Cyanidin-3-glucoside alleviates 4-hydroxyhexenal-induced NLRP3 inflammasome activation via JNK-c-Jun/AP-1 pathway in human retinal pigment epithelial cells." Journal of immunology research 2018 (2018).

7. Marchesi, Nicoletta, et al. "Autophagy stimulus promotes early hur protein activation and p62/SQSTM1 protein synthesis in ARPE-19 cells by triggering erk1/2, p38mapk, and JNK kinase pathways." Oxidative medicine and cellular longevity 2018 (2018).

8. Kyosseva, Svetlana V., et al. "Nanoceria inhibit expression of genes associated with inflammation and angiogenesis in the retina of Vldlr null mice." Experimental eye research 116 (2013): 63-74.

9. Kalariya, Nilesh M., et al. "Cadmium-induced apoptotic death of human retinal pigment epithelial cells is mediated by MAPK pathway." Experimental eye research 89.4 (2009): 494-502.

10. Sun, Y., and Y. X. Liu. "LncRNA HOTTIP improves diabetic retinopathy by regulating the p38-MAPK pathway." Eur Rev Med Pharmacol Sci 22.10 (2018): 2941-2948.

11. Zhu, Yan-Ni, et al. "The involvement of the mGluR5-mediated JNK signaling pathway in rats with diabetic retinopathy." International ophthalmology 39.10 (2019): 2223-2235.

12. Wang, Hao, et al. "Salusin-β Mediates High Glucose-Induced Inflammation and Apoptosis in Retinal Capillary Endothelial Cells via a ROS-Dependent Pathway in Diabetic Retinopathy." Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 14 (2021): 2291.

13. Kaikai, Shen, et al. "Critical role of c-Jun N-terminal kinase in regulating bFGF-induced angiogenesis in vitro." The Journal of Biochemistry 150.2 (2011): 189-197.

14. Zhuang, Xiaonan, et al. "SHP‐1 suppresses endotoxin‐induced uveitis by inhibiting the TAK1/JNK pathway." Journal of cellular and molecular medicine 25.1 (2021): 147-160.

15. Hu, Dan-Ning, et al. "Constitutive and LPS-induced expression of MCP-1 and IL-8 by human uveal melanocytes in vitro and relevant signal pathways." Investigative ophthalmology & visual science 55.9 (2014): 5760-5769.

16. Lee, I-Ta, et al. "TNF-α mediates PKCδ/JNK1/2/c-Jun-dependent monocyte adhesion via ICAM-1 induction in human retinal pigment epithelial cells." PLoS One 10.2 (2015): e0117911.

17. Qin, Tingyu, and Shasha Gao. "Inhibition of proteasome activity upregulates IL-6 expression in RPE cells through the activation of P38 MAPKs." Journal of ophthalmology 2018 (2018).

18. Wu, Wen-Chuan, et al. "Subtoxic levels hydrogen peroxide-induced production of interleukin-6 by retinal pigment epithelial cells." Molecular vision 16 (2010): 1864.

19. Messerschmidt, Luise, et al. "Osmotic induction of cyclooxygenase-2 in RPE cells: Stimulation of inflammasome activation." Molecular vision 25 (2019): 329.

20. Adhikary, Gautam, Yan Sun, and Eric Pearlman. "C‐Jun NH2 terminal kinase (JNK) is an essential mediator of Toll‐like receptor 2‐induced corneal inflammation." Journal of leukocyte biology 83.4 (2008): 991-997.

21. Jiang, Yida, et al. "Critical role of caveolin-1 in ocular neovascularization and multitargeted antiangiogenic effects of cavtratin via JNK." Proceedings of the National Academy of Sciences 114.40 (2017): 10737-10742.

22. Sun, Hui, et al. "Protective effect of a JNK inhibitor against retinal ganglion cell loss induced by acute moderate ocular hypertension." Molecular vision 17 (2011): 864. 

23. Li, Ning, Yuehua Li, and Xuanchu Duan. "Heat shock protein 72 confers protection in retinal ganglion cells and lateral geniculate nucleus neurons via blockade of the SAPK/JNK pathway in a chronic ocular-hypertensive rat model." Neural regeneration research 9.14 (2014): 1395.

24. Cai, Xue, Sudipta Seal, and James F. McGinnis. "Sustained inhibition of neovascularization in vldlr−/− mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-κB pathway." Biomaterials 35.1 (2014): 249-258.

25. Guma, Monica, et al. "Genetic and pharmacological inhibition of JNK ameliorates hypoxia-induced retinopathy through interference with VEGF expression." Proceedings of the National Academy of Sciences 106.21 (2009): 8760-8765.

26. Jauhonen, Hanna-Mari, et al. "Cis-urocanic acid inhibits SAPK/JNK signaling pathway in UV-B exposed human corneal epithelial cells in vitro." Molecular vision 17 (2011): 2311.

27. Li, Hongying, et al. "Lycium barbarum (wolfberry) reduces secondary degeneration and oxidative stress, and inhibits JNK pathway in retina after partial optic nerve transection." PLoS One 8.7 (2013): e68881.

28. Du, Shaobo, et al. "Lycium barbarum polysaccharides protect rat corneal epithelial cells against ultraviolet B-induced apoptosis by attenuating the mitochondrial pathway and inhibiting JNK phosphorylation." BioMed research international 2017 (2017).

29. Wang, Ying, et al. "Sodium formate induces autophagy and apoptosis via the JNK signaling pathway of photoreceptor cells." Molecular medicine reports 13.2 (2016): 1111-1118.

30. Whitmore, Hannah AB, et al. "TNF‐α signaling regulates RUNX1 function in endothelial cells." The FASEB Journal 35.2 (2021): e21155.

31. Lin, Fan-Li, et al. "Theissenolactone C exhibited ocular protection of endotoxin-induced uveitis by attenuating ocular inflammatory responses and glial activation." Frontiers in pharmacology 9 (2018): 326.

32. Eshac, Youssof, Rachel L. Redfern, and Vinay Kumar Aakalu. "The Role of Endogenous Antimicrobial Peptides in Modulating Innate Immunity of the Ocular Surface in Dry Eye Diseases." International Journal of Molecular Sciences 22.2 (2021): 721.

33. Musi, Clara Alice, et al. "JNK3 as therapeutic target and biomarker in neurodegenerative and neurodevelopmental brain diseases." Cells 9.10 (2020): 2190.

34. Miller, William P., et al. "Activation of the stress response kinase JNK (c-Jun N-terminal kinase) attenuates insulin action in retina through a p70S6K1-dependent mechanism." Journal of Biological Chemistry 292.5 (2017): 1591-1602.

35. Park, Hye Ji, et al. "JNK pathway is involved in the inhibition of inflammatory target gene expression and NF-kappaB activation by melittin." Journal of inflammation 5.1 (2008): 1-13.

36. Li, De-Quan, et al. "JNK and ERK MAP kinases mediate induction of IL-1β, TNF-α and IL-8 following hyperosmolar stress in human limbal epithelial cells." Experimental eye research 82.4 (2006): 588-596.