Targeting Bruch’s Membrane

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.”

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.

Maximilian Pfau MD, PhD is the Head of the Visual Neurophysiology Platform, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Switzerland. maximilian.pfau@iob.ch, maximilian.pfau@nih.gov