Hydrogels have been making noise as a novel drug delivery mechanism in ophthalmology in recent years, and an ingenious innovation out of South Korea in retinitis pigmentosa (RP) might just take this promising tech to new heights.
The breakthrough research, published in Nature’s NPJ Regenerative Medicine, features an inflammation-responsive hydrogel (IRH) drug delivery system for RP, and could push the boundaries of what is possible in delivering therapeutics to the back of the eye.1
Led by Dr. Maesoon Im of the Korea Institute of Science and Technology (KIST), the collaborative work of the investigating team has intriguing potential applications not only for certain inherited retinal diseases (IRDs), but also for other inflammatory retinal ailments.
The hyaluronic acid-based hydrogel served as a vehicle for an anti-inflammatory epigenetic drug, an enhancer of zeste homolog 2 (EZH2) inhibitor. The hydrogel itself was found to effectively deliver the medication directly to the retina in response to intraocular inflammation, as demonstrated in both in vitro experiments and tests conducted on mice with retinal degeneration—a model for RP.
The study was headlined by two key results. Not only did treatment with EZH2 inhibitor-loaded IRH reduce inflammation within the retina, but it also safeguarded the morphological and functional integrity of photoreceptors in the eyes of treated animals. These findings suggest the potential of the IRH as a therapeutic intervention to mitigate the progression of diseases like RP.1
In addition to the use of an EZH2 inhibitor, the buzz surrounding the research involved the clever design behind the IRH itself. Sustained drug delivery devices, such as those starting to see use in glaucoma, slowly release therapeutics over time into the eye. The novel IRH, however, delivers drugs like EZH2 in response to inflammation itself, improving efficacy and adding to the longevity of the hydrogel in the eye.
This is especially critical in a lifelong IRD like RP, which is characterized by the progressive deterioration of photoreceptor cells in the retina. There are multiple gene therapy candidates for the disease targeting its genetic cause, but there is currently no effective cure.
The newly-developed IRH offers a promising alternative by targeting the symptoms of inflammatory retinal diseases as pathological damage is about to occur, as it delivers medication in response to sight-robbing inflammation.
Implications beyond RP
This sort of intraocular application is a big part of why hydrogels have been making so much news of late. While they’ve been used in the eye care field going back to the 1960s, forming the moisture-retaining structure of soft contact lenses, the biggest waves hydrogels have been making lately have been in advanced applications within the eye.
The unique ability of hydrogels to retain fluids in a porous polymer structure makes them ideally suited to such applications in the vitreous. They have been found effective in helping medicines reach retinal tissue that would otherwise have rejected a foreign medium, and can serve as tissue-engineered constructs for repairing and regenerating ocular tissues. Recent research has shown they can even be useful as an adhesive within the eye, or as a replacement for vitreous itself.2
But it’s their use in ophthalmic drug delivery systems, as in the study above, where hydrogels have been making the biggest impact in recent years.
Because their structure allows hydrogels to release drugs slowly over time, they can provide sustained therapeutic effects while reducing the need for frequent administration. And with this study’s IRH innovation, this sustained release can now effectively be programmed to be on-demand for the most critical time in a disease’s detrimental effects on a patient’s vision.
The use of cases for such a mechanism go far beyond RP and other inflammatory IRDs. For patients with other inflammatory eye diseases, an IRH delivery system would entail fewer trips to the clinic, and fewer uncomfortable injections.
This goes far beyond convenience and comfort alone. Compliance remains a very serious concern among retina specialists whose patients’ condition requires intraocular injections. In these cases, where patients do not always receive all of the regular injections their illness requires, a longer-term delivery system such as one involving hydrogels can be very significant in reducing vision loss overall.
More hydrogel therapies on the horizon
The research out of South Korea, however, is another promising piece of research in a recent surge of tantalizing ophthalmic hydrogel innovations. Researchers are pursuing more ambitious use for hydrogels, aiming to not just reduce, but do away with intraocular injections altogether in treating retinal disease.
One such application for hydrogel delivery systems is through the use of intraocular implants. Though implant systems are not entirely non-invasive, they do create a far more comfortable and long-lasting method of drug delivery by placing a refillable implant within the eye to dispense drugs as needed.
Axpaxli, one such durable implant developed by Ocular Therapeutix (Massachusetts, USA), uses hydrogels to deliver axitinib for the treatment of neovascular (wet) age-related macular degeneration (nAMD), diabetic retinopathy (DR), and other retinal diseases. Having received FDA permission to undergo research trials in early 2023, the implant’s developers announced that they had begun Phase 3 patient screenings on February 13 of this year.3
The potential availability of a hydrogel-based implant delivery system would be a welcome addition to the retina specialist’s toolkit, and a boon for patients hoping for an alternative to regular injections.
Other researchers are looking to use hydrogels to take posterior delivery systems out of the surgical theater altogether and into the world of eyedrops. Kyowa Kirin (Tokyo, Japan) announced on February 6, 2024 that it had begun phase 2 trials on KHK4951, a novel nano-crystalized tivozanib eye drop designed to deliver the drug to the posterior ocular tissues for the treatment of diabetic macular edema (DME).4
These hydrogel-based drops may be useful in delivering treatment options for other conditions of the retina as well. Kyowa Kirin also announced that a separate Phase 2 study to evaluate KHK4951 in patients with nAMD is also being initiated, and is currently recruiting patients.4
The availability of less-invasive and completely non-invasive treatment options for those who suffer from the biggest threats to patients’ retinal health would be a welcome change indeed, and hydrogels are key to these future developments. These remarkable materials can provide critical, targeted and on-demand treatments to the posterior segment while maintaining a high standard of patient comfort and compliance. This all could mean a new era in protecting vision is just on the horizon.
References
- Kim H, Roh H, Kim SH, Lee K, Im M, Oh SJ. Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration. NPJ Regen Med. 2023;8(1):68.
- Lin KT, Wang A, Nguyen AB, Iyer J, Tran SD. Recent Advances in Hydrogels: Ophthalmic Applications in Cell Delivery, Vitreous Substitutes, and Ocular Adhesives. Biomedicines. 2021;9(9):1203.
- Ocular Therapeutix Press Release. Available at: https://investors.ocutx.com/news-releases/news-release-details/ocular-therapeutixtm-announces-first-subjects-screened-phase-3 Accessed on 27 February 2024
- Kyowa Kirin Press Release. Available at: https://www.kyowakirin.com/media_center/news_releases/2024/pdf/e20240206_01.pdf Accessed on 27 February 2024