Retinal Regeneration Study Shows Encouraging Early Results

Phase 1 trial demonstrates therapeutic benefit without damage to the targeted structure

Retinal Regeneration Study Shows Encouraging Early Results

Phase 1 trial demonstrates therapeutic benefit without damage to the targeted structure.


Three decades of retina research focused on photoreceptor cells and the retinal pigment epithelium (RPE) have led to the development of nonthermal Ellex (Adelaide, Australia) Retinal Regeneration Therapy (2RT). This investigational modality has, in a recent early trial, provided data that demonstrate potential to improve and stabilize visual acuity (VA) and reduce retinal edema in patients with diabetic maculopathy and macular edema without causing damage to the photoreceptors (Figure 1). The brainchild of ophthalmic laser pundit Professor John Marshall (Frost Professor of Ophthalmology and Head of the Academic Department of Ophthalmology at the Rayne Institute King's College, University of London) and Malcolm Plunket and Victor Previn, scientists with Ellex's advanced research group, Ellex's 2RT showed encouraging results in an early pilot study and is poised to begin the second phase.

Prof. Marshall says these early outcomes suggest that 2RT has the potential to change the way diabetic maculopathy is treated and that the modality shows promise for sight-saving intervention in early stage age-related macular degeneration (AMD). Here is an explanation of how the 2RT works.


The 2RT laser is a Q-switched green YAG laser that has a wave length of 532 nm. It has the distinction of having a very short pulse duration of 3 nanoseconds and pulse energy of 10 microjoules per pulse. The 2RT laser facilitates photoregeneration, which refers to laser therapy that stimulates a natural biologic response in the eye to produce a therapeutic benefit without causing damage to the eye's sight-generating structures. "The ultimate goal here is to use this system prophylactically to minimize the retinal aging process so that the onset of AMD genes do not result in clinical symptoms," Prof. Marshall says.

Professor Marshall reports a significant financial interest in Ellex. Mr. Hamilton reports no financial interest in Ellex.

Prof. Marshall's vision of 2RT's future is built on Bruch's membrane and the effects caused by the membrane's aging process.

"The aging process changes Bruch's membrane such that it becomes thicker and accumulates debris. Because of this, the ability of water to move out of the neuroretina into the choroid decreases exponentially, and the ability of vital metabolites to move in the opposite direction decreases linearly," Prof. Marshall explains.

"Furthermore, diseases that involve fluid accumulation in the retina tend to be related to the fact that the fluid can't get out quickly enough because of the debris in Bruch's membrane."

From this, Prof. Marshall deduced that even those who do not have a genetic predisposition to AMD would eventually have significant retinal problems if they lived long enough, merely as a result of the aging process. "Some individuals, purely as a result of aging, reach a critical point in this degenerative change by their late 80s," he says.

Marshall postulated that if the rate of retinal degeneration could be speeded up by certain high-risk environmental factors such as cigarette smoking, and possibly diet and excessive light exposure, then perhaps regeneration was possible as well. "Based on this, I and my colleague Ali Hussein began to consider that if we could reduce the rate of retinal aging in people who have an AMD gene, then perhaps the gene would not manifest symptoms during the person's lifetime," explains Prof. Marshall.

Figure 1. Scan shows improvements effected by 2RT treatment.

With the goal of "cleaning up Bruch's membrane," to regenerate the retina, Prof. Marshall and colleagues discovered that use of a very low intensity laser for a very short time period instigated a chain of events that enabled the researchers to attain their desired result.

"We found that we could cause about 15% to 20% of the epithelial cells that we hit with the laser to relocate themselves, and in order to relocate themselves they excrete onto Bruch's membrane MMP2 and MMP9, 2 types of matrix metalloprotease enzymes, which clean up Bruch's membrane and then later release growth factors," Prof. Marshall says. "These growth factors defuse forward into the retina and essentially turn off the taps of the leaky retinal capillaries. The initial clinical trial aimed to see whether we could clear the fluid in diabetic macular edema. The outcomes confirmed, that yes, we could do that without any damage to photoreceptor cells."


The clinical trial is being directed by Mr. Peter Hamilton of St. Thomas Hospital, London, and Prof. Marshall. The prospective study, which included 29 eyes of 18 patients, was designed to evaluate the efficacy of selective RPE treatment (2RT) in diabetic maculopathy with macular edema. The duration of the study was 3 months with patient follow-up at 3 weeks, 6 weeks and 3 months post-treatment.

All patients received treatments with the Ellex 2RT prototype lasers that were developed specifically for research of the new method and technology.

Optical coherence tomography (Figure 2) showed a decrease in CMT following treatment with 2RT.

In addition, microperimetry confirmed that there was no evidence of laser damage to the photoreceptor cells. Regeneration of the pigment epithelium begins to show about 7 days after treatment, according to Mr. Hamilton.

"These were quite encouraging results," says Mr. Hamilton. "We were trying to get rid of the retinal edema, and that is what we achieved.

"We started out initially putting 120 microjoules per square centimeter, and we found that that was creating a reaction on the pigment epithelium, so we cut it down significantly to 60 microjoules per square centimeter," explains Mr. Hamilton.

The weaker treatment resulted in the desired outcome. There was no visible reaction on the pigment epithelium and there was reduction in macular edema.

Even in one of the few instances where leakage increased, Mr. Hamilton points out, the treatment still provided a benefit. "We got an improvement of the LogMAR VA from 0.3 to 0.1," says Mr. Hamilton.


There has been an evolution of retinal laser treatments from very heavy burns that did the job but scarred the retina to today's 2RT, "which just tickles the pigment epithelium," according to Mr. Hamilton. "Laser burns — even moderate laser burns — tend to expand, so with time it's possible for the burn to extend under the macula," he says. "So it's obvious that 2RT is much less destructive to the retina, and if it continues to show the promise that it has already shown, and I cannot see any reason why it shouldn't, then this will be the way forward."

"Laser burns — even moderate laser burns — tend to expand, so with time it's possible for the burns to extend under the macula."
— Mr. Peter Hamilton

Another advantage of 2RT is that it targets and treats only the pigment epithelium.

"Because of this we can treat very close to the center of the vision, whereas with conventional lasers it's difficult to treat close to the center because there's a possibility of getting damage to the fovea," Mr. Hamilton points out.


The only disadvantage of the 2RT laser treatment, according to Mr. Hamilton, is that because it leaves no visible reaction on the pigment epithelium it is impossible to determine exactly what areas have already been treated. "When we do fluorescein angiography we still can not see any reaction," says Mr. Hamilton. "Hopefully, we are going to develop a system that will enable us to record exactly where the burns have been applied, so that we won't have to rely on memory to avoid retreating over the top of an existing burn." Mr. Hamilton says he suspects that the encouraging results from the first phase of the clinical study will undoubtedly influence the development of such a system sooner rather than later.

Figure 2. CMT shows improvement in visual acuity and central macular thickening following 2RT treatment.

"It's important to keep in mind that 2RT research is in the very early phase, so we really have a lot more work to do. We would like to use the system to treat patients with panretinal photocoagulation as well as some patients with peripheral new vessels," says Mr. Hamilton.

Prof. Marshall says that prophylactic use of 2RT would first be directed at high-risk patients. This would include "individuals with high levels of autofluorescence of lipofuscin in their pigment epithelium," he says. However, he adds that given that there are no manifestations of the effect of the laser on the patient's vision, it could theoretically be made available to anyone who wants the benefits of retinal rejuvenation.

Prof. Marshall points out that it is easy to lump all retina lasers together, but they are not all the same, and 2RT is unique. "In the past, conventional lasers have been used to treat drusen, and that's been singularly unsuccessful for several reasons," he says. "First, because there's a risk vs benefit because the laser energy that is used to get rid of the drusen kills the photoreceptor cells as well, and those are the very cells you're trying to save. So very few lesions are put in and they're placed far away from the central area, which is what they want preserved," says Prof. Marshall.

Further, he cited well-known data showing that even slight overtreatment of drusen can trigger new vessel formation.

The Ellex 2RT modality is quite different from that of earlier laser modalities, explains Prof. Marshall, because it does not treat drusen. "It will be treating very large numbers of irradiations diffusely over a large area, and the treatment will be very close to the center of the macula because, as we've shown in the early clinical study, 2RT has no effect on the photoreceptor cells." RP