Can Early Laser Therapy Delay Disease Progression?

The pioneer of short-pulse “Retina Regeneration Therapy” explains the theory and early results.

JOHN MARSHALL, PhD, FRCPATH, FRCOPHTH

In any age-related disease, you have to reconcile the fact that the system works perfectly well for 60 or 70 years and then performance begins to decline or comes to a complete stop. The reasons are always complex and multifactorial. Much of the current research into age-related macular degeneration focuses on identifying genes that can be linked to the disease. To date, more than 34 genes have been linked to AMD, six in Bruchs membrane alone.

Obviously this work is important. However, recognizing that there is a genetic component, you have to stop and ask why — even with a defective gene present — does the system work so well for so long? It is for this reason that I have been involved in developing a new approach to laser treatment in retinal disease, one that allows us to intervene earlier and without the worry of collateral damage that exists with currently used laser treatments.

THE GENE FACTOR

When considering the relationship between genetics and AMD, a couple of points bear mention. First, we all have different rates of aging governed by our genes. So you can have “good” genes, look really young, and live until you are 100, or you can have “bad” aging genes, and they will crash the system much earlier — say, age 65 to 70.

Second, we also know that environmental factors come into play as part of the aging process. If you have good genes but you smoke, you're going to cause the system to crash earlier than if you didn't smoke. If you have bad genes and you smoke, you will cause the system to crash even earlier still.

A third factor concerns the gene itself. Visualize a graph that shows your life from birth to 100, with “age” on the X-axis, and let's call it “quality of vision” on the Y-axis. As you age, your genes cause the graph's slope to gradually decrease. If there is a bad gene in the mix, such as one that causes AMD, it's going to cause decline at a greater degree, but generally not until you've reached the age of 60 to 70.

With the new laser approach that we've been developing, the idea is to push up the slope of the aging process by rejuvenating the part of the system that's starting to fail — in this case, the RPE cells and Bruchs membrane. If we're right, and therapy can push the curve up high enough, that means even if genetic factors do reduce the curve's slope it won't take effect until it really doesn't matter.

WHAT IS ELLEX 2RT?

2RT refers to Retina Regeneration Therapy, a non-thermal, short-pulsed laser treatment undergoing clinical study by Ellex of Adelaide, Australia, in early-stage diabetic macu-lopathy, macular edema, and AMD. The laser used is a specially designed, Q-switched, green Nd:YAG with a wavelength of 532 nm. Its pulse duration is three nanoseconds with energy of around 200 μJ per pulse. This is one of the key differences with this laser: Instead of using millisecond or microsecond treatment times, this treatment is in nano seconds, so it's using extremely fast pulses. In addition, we have taken a different approach by using large spots of 400 μm instead of the traditional top-hat or Gaussian-shaped laser beam and 50-μm spot size commonly used for retinal lasers. Another key difference is that all laser energy is designed to stay within the RPE cells. Only about 10% to 15% will go above the damage threshold, but that is enough to open up little holes and allow the remaining cells to migrate.

When those cells do migrate, they will release matrix metalloproteinase (MMP). The MMP phase reaches its peak at three to five days after treatment, and then, at seven to nine days, some of the RPE cells will divide. When this occurs, it triggers what we describe as photorejuvenation of the RPE and Bruch's membrane, the areas responsible for keeping retinal function optimized. This is done without causing damage to peripheral areas. More importantly, it can be used in the central retina without photoreceptor damage.

Initially, 2RT will be performed in high-risk patients in their 40s and 50s, hopefully rejuvenating the transport function of Bruch's membrane so that, if defective genes appear, the baseline performance isn't sufficiently depressed. This should suppress the onset of further AMD development. If we get it right, we won't see any neovascularization.

FIRST CLINICAL RESULTS

The first clinical study was performed in patients with diabetic maculopathy and/or macular edema here in London at St. Thomas' Hospital and involved 29 eyes of 18 patients. Patients are being followed for one year. Postoperative testing includes optical coherence tomography and microperimetry.

At the six-month follow-up, 17 patients (28 eyes) were available. The LogMar visual acuity had improved by two or more lines in 43% of eyes and between one and two lines in 28%. It remained unchanged in 15% of eyes, and deteriorated by two or more lines in 14%. Central macular thickness decreased by more than 5% from baseline in 46% of patients, remained stable in 39%, and had an increase of more than 5% in 15% of patients. The number of hard exudates decreased in 41% of eyes, stayed stable in 43%, and increased in 16%. Vascular leakage decreased in 55% of eyes, was unchanged in 31%, and increased in 14%. Slit-lamp ophthalmoscope microperimetry confirmed that photoreceptor function was not affected by the laser treatment. No adverse effects occurred during the study period.

Porcine RPE following 2RT laser treatment. Calcein-AM was used to visualize living RPE cells (green) and dead RPE cells (black) within the Ellex 2RT treatment spot (red circle). Cell membranes are not ruptured and no collateral damage is caused to photoreceptors.

WHY THE SHORT-PULSE APPROACH?

In the past, with laser treatments using conventional systems, people have tried to treat one major early manifestation of AMD by directly treating drusen. This is bad news for a number of reasons. First, with a conventional laser, the moment you fire at the outer retina, you're killing the very cells that you're trying to preserve: the photoreceptor cells. Second, it's not a good idea to fire at drusen because they are focal expressants of Bruch's membrane when it is at its worst. So if you fire the laser in there, it could potentially cause further breakdown in the membrane and thus lead to new neovascularization — exactly opposite of the desired effect.

There's another distinction between Ellex 2RT and a more conventional approach. Because these lasers are quite powerful and destructive, typically the number of treatment spots is minimal (perhaps 12 to 15 lesions) and none fall in the central area to avoid destroying central vision. The team behind the development of 2RT believes that this approach treats the wrong anatomical target, because it's the whole of Bruch's membrane that's affected as a function of aging. You don't want to pick out the drusen for selective therapy; you want a diffuse treatment of the whole area.

CONCLUSION

I'll leave you with one final point to consider. All FDA-approved AMD treatments today are only suitable for advanced or end-stage disease. Rather than intervene at the level of the underlying pathology they address complications associated with the disease. It is our hypothesis that Ellex 2RT gives us the opportunity to apply a gentler treatment earlier in the disease process that may well prevent neovascularization and progression to wet AMD. Time will tell. RP