TARGETING BRUCH’S MEMBRANE

Three therapeutic approaches targeting Bruch’s membrane under evaluation.

BY DR GEARÓID TUOHY

Speaking at the 22nd EURETINA Congress in Hamburg, Germany, Dr Maximillian Pfau discussed three therapeutic approaches targeting Bruch’s membrane: vitamin A supplementation, removal of Bruch’s membrane deposits, and a surgical bypass process using a choroid Bruch’s membrane RPE patch.

Bruch’s membrane provides a structural support and attachment for the retinal pigment epithelium (RPE), a semi-permeable filtration barrier that provides metabolic exchange between these layers. Nutrients pass from the choriocapillaris through Bruch’s membrane to reach the RPE and the photoreceptors. Cellular breakdown products may travel in the opposite direction. Diffusion through Bruch’s membrane depends on the local concentration of salts, glucose, and pH.

The membrane is 2 µm to 4 µm thick for adults and can change in thickness, ultrastructure, and histochemistry with age and disease. Changes are associated with the accumulation of material thought to derive from the highly metabolically active RPE, where it functions as the “household calvary” to degrade photoreceptor outer segment (OS) shed tips. The undigested end products are collected by phagocytosis and subsequently fuse with long-term phagosomes and the breakdown materials. These are then recycled and extruded through the basal surface of the RPE into Bruch’s membrane before diffusing into the choroidal circulation. With age and disease, the level of waste materials may lead to drusen formation in age-related macular degeneration and other disorders.

Adding vitamins

One approach Dr Pfau told delegates was a supplementation strategy that essentially pushes vitamin A through the choroid and Bruch’s membrane, even in the context of degenerating layers, to provide as much vitamin A as possible via elevating blood levels. Sorsby fundus dystrophy patients in Philadelphia,

Pennsylvania, US, first received this therapy, whereby vitamin A supplementation used approximately 50,000 units for one month—and it provided significant improvements in the dark adaptation (DA) kinetics.

A similar approach using vitamin A for late-onset retinal degenerative (L-ORD) patients showed a comparable improvement in DA kinetics. A further study with Pseudoxanthoma elasticum (PXE) patients, with a progressive calcification of elastic fibres, also showed moderate vitamin A levels could improve similar DA kinetics.

In healthy aged eyes and eyes with early AMD, a landmark trial by Cynthia Owsley and colleagues demonstrated small improvements are attainable with high-dose vitamin A supplementation. And while the effect size of the study was small and many of the eyes in the cohort had relatively healthy retina, patients showed a number of improvements. Lastly, Dr Pfau mentioned a current study with an intermediate-AMD group—conducted at the US National Eye Institute (NEI, PI: Catherine A Cukras MD, PhD)—using a moderate and high dose supplementation with vitamin A is expected to publish its results soon.

Cleaning up the mess

A second strategy is a potential therapeutic treatment aimed at clearing up Bruch’s membrane with a deposit removal approach, using both an exogenous and endogenous process.

The endogenous strategy (“stimulating repair”) applies a nanosecond laser treatment to up-regulate proteases and thin the membrane. LEAD study (NCT01790802) results reported no significant effect on slowing AMD progression for the relevant endpoints (adjusted hazard ratio [HR], 0.61 [0.33–1.14], p = 0.122). Dr Pfau added that the post-hoc analyses of the trial suggest a therapeutic window for using laser treatment depending on the stage of disease.

The exogenous process, on the other hand, uses apolipoprotein (apo) A-I mimetic peptides (e.g., L-4F). These short helical peptides (18 amino acids; molecular weight, 2.31 kDa) may emulate anti-atherogenic properties of apoA-I (243 amino acids, 28.3 kDa), and these amphipathic peptides sequester lipids for travel through aqueous environments. The L-4F has reported binding with high-affinity oxidized phospholipids and fatty acid hydroperoxides in cellular membranes and is well tolerated by humans, providing an attractive strategy for targeting Bruch’s membrane lipids and soft drusen. This approach targets thinning the Bruch’s membrane and, in preliminary preclinical work, has shown the clearing up of neural lipid, esterified cholesterol, and membrane attack complex.

Dr Pfau reported this particular mimetic peptide approach is not under clinical consideration this year, but others have potential in the future. Regardless, this was just one peptide, and there may be new or improved compounds in the pipeline.

A last resort

The last strategy is what Dr Pfau commented as the “last and most drastic” therapeutic option—a surgical bypass.

“It’s mostly obsolete these days, and is a strategy for having a full choroid/ Bruch’s membrane/RPE patch, explanting that from the peripheral retina and moving it below the fovea to save the fovea from further degeneration.”

Prof Bernd Kirchhof, now retired, presented this surgical approach approximately 15 years ago in Cologne, Germany. One follow-up patient had an intact patch with a reasonable visual acuity measurement of 0.4 logMAR, indicating some level of function.

There are multiple approaches targeting the barrier at Bruch’s membrane. Short-term vitamin A supplementation may be effective to restore rod-mediated dark adaptation, which the results of an ongoing trial should reveal in due course.

“For the vitamin A trials, there is clearly a signal there, but it’s a little bit difficult to understand [the data],” Dr Pfau told delegates. “They enrolled patients with different disease stages, and it’s unclear at what disease stage vitamin A provides the best benefit or if it is more for a short diagnostic test.”

Vitamin A supplementation can provide significant improvements in dark adaptation kinetics.

Post-hoc analyses suggest a therapeutic window for using laser treatment.

The LEAD clinical study did not provide an effective outcome for nanosecond laser treatment to date, although there may be an appropriate therapeutic window for this approach. Notably, such a new trial examining nanosecond laser again is currently in the planning stages. For the apoA-I mimetic peptides, again, the outcome to date has only progressed to the preclinical stages, but new iterations in lab studies could address peptides in the future.

Finally, autologous transplantation of a choroid Bruch’s membrane RPE patch is successful for selected patients. “But there is no evidence that the benefit on average outweighs complications,” Dr Pfau concluded.

Rayner creates outcomes app

Rayner announced the global launch of RayPRO+, a free smartphone app that collects patient-reported outcomes for up to three years after cataract surgery. Patients register in the surgeon’s office—where the surgeon records the type of lens implanted—and then answer a few questions on their satisfaction, spectacle independence, dysphotopsia, and follow-up procedures. Using the RayPRO+ dashboard the surgeon can then analyse the responses and trends about patients, clinics, and IOLs. The company suggests the app can be used for several purposes, including peer comparison, clinical studies, and promotion of surgical services to new patients.

www.rayner.com

Ocular corticosteroid nanoemulsion

Salvat Laboratories announced the submission of NDA documentation for a new drug application to the US FDA for approval of Clobetasol. It would be the first ocular corticosteroid formulated in a nanoemulsion for inflammation and pain in patients undergoing eye surgery. The Spanish company has created a proprietary nanoemulsion technology it says enhances drug penetration and bio-adhesion while enhancing patient comfort. In clinical trials, the drug had no rebound effect two weeks after treatment. The product does not need to be shaken because the nanoemulsion ensures a consistent concentration.

Svt.com

OK for Omlonti

Santen announced US FDA approval of Omlonti® (omidenepag isopropyl ophthalmic solution) 0.002% eyedrops for reducing elevated intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension. Omidenepag isopropyl, the active pharmaceutical ingredient, is a relatively selective prostaglandin EP2 receptor agonist, which increases aqueous humour drainage through the conventional (or trabecular) and uveoscleral outflow pathways. It is currently the only product with this pharmacological action, the company said.

santen.com

Nidek launches non-contact tono/ pachymeter

Nidek has launched an innovative non-contact tonometer/pachymeter, the NT-1p. The device automates reliable non-contact tonometry and pachymetry. After the patient puts their chin on the chinrest, the NT-1p recognises the eye position automatically and starts measuring without a user prompt.

The product offers flexibility via a variety of options. There are models with and without joysticks. The newly designed joystick’s four-direction button provides seamless movement of the measurement device, while the addition of handheld control and tablet control software allows for remote operation. nidek.com

New dry eye treatment advances

Aldeyra Therapeutics took a step closer to US FDA approval of reproxalap, its novel drug candidate intended for dry eye disease treatment. The company submitted a new drug application (NDA) based on extensive clinical trial data. This would be the first approval of a RASP (reactive aldehyde species) modulator, a family of small molecule targets that affect a broad array of protein mediators.

www.aldeyra.com

Data modelling with decision trees and multiple regression analysis identified the contributions personality traits made. Low neuroticism and high extraversion were the primary personality contributors for men, while in women, all traits contributed. Women had higher expectations for postoperative distant acuity than men (0.1 vs 0.2 logMAR) to present high satisfaction. Both groups showed openness, conscientiousness, and extraversion as contributors to optimal satisfaction.

N Panagiota et al., “Impact of personality on the decision process and on satisfaction rates in pseudophakic presbyopic correction”, 48(12): 1433–1439.