The Challenges of Drug Delivery for Retinal Diseases - Episode 7
Challenges associated with delivering therapies currently available to treat retinal disorders and methods being explored to improve drug delivery to patients.
Albert J. Augustin, MD: We’ll move forward and speak a little about challenges of drug delivery. We already heard a little about this. We agree that the complex anatomy and physiology of the eye makes it a challenge. If we want to overcome the monthly intravitreal injections of different drugs, we need to get access to the retina in terms of obtaining therapeutic drug concentrations. We agree that a challenging task of drug delivery is to overcome the ocular barriers and deliver drugs efficiently to the targeted ocular tissue. This is true not only for the retina but maybe also for the choroid and other intraocular tissues.
The drugs are usually prevented from reaching the ocular tissues by static and dynamic biological ocular barriers. These barriers can be classified or ordered depending on their anatomical location and their functional properties. This means, in general, these barriers can also be classified as interior and posterior segment barriers. In addition to this, we must differentiate between static and dynamic ocular barriers. The static ocular barriers are corneal epithelium, the blood-aqueous barrier, the sclera, the retinal pigment epithelium, and the blood capillary endothelial cells. In addition, the dynamic ocular barriers consist of the tear drainage, conjunctival blood and lymph clearance, and choroidal blood and lymphatic circulations.
Dr Moosajee, can you please review how the blood-retinal barrier is disrupted to allow oral delivery, and how you can overcome this? In addition, I’d like you to discuss a little about the reformulation and penetration to direct drug-delivery systems.
Mariya Moosajee, MBBS, BSc, PhD, FRCOphth: Thank you. With inherited retinal dystrophies, the photoreceptor and the RPE [retinal pigment epithelium] layer are the main target layers affected in the disease process, with the end stage being cell death. We very rarely see areas of intact RPE when the photoreceptors have diminished. You can also see these accompanying changes with the choriocapillaris in certain conditions. The blood-retinal barrier, as you very nicely overviewed, has 2 main components. From the posterior side it’s that retinal vascular endothelium and the retinal pigment epithelium; hence, if the RPE is disrupted, we will disturb this barrier. Orally administrated drugs may then be able to penetrate into the retina more easily, especially if those are small-molecule drugs.
In the IRD [inherited retinal diseases] space, several clinical trials are giving drugs, particularly neuroprotectants. For example, a drug called N-acetyl cysteine, which is a high-dose antioxidant and is in phase 2 clinical trials for retinitis pigmentosa. It’s orally administrated, and we’re hopeful that it penetrates into those target cell layers. With regard to reformulation and penetration into the retina, ideally we want to give the drugs to the target tissue: the retina itself. A lot of these drugs may need to be reformulated; therefore we need to do pharmacokinetics and toxicology studies to determine safety penetration half-life and the dosing regimen. The benefit is that we can avoid systemic exposure and potential adverse effects. On the flip side, from some of the work I’ve done and with AMD, there have been whole metabolomic profiling studies that have looked at the metabolites in the blood. For example, in patients with choroideremia we found high levels of oxidative stress, disrupted lipids, and serotonin dysfunction. In these cases, they may not just be isolated eye conditions. There may be a systemic effect, so systemic delivery may not be a bad thing.
Transcript edited for clarity.