Where Are We Now?

A Summary of a Quarter-Century of Low Vision Research and Development

Presented to the International Low Vision Support Group
by Dan Roberts, Director

Macular Degeneration Support, the charitable parent corporation of our International Low Vision Support Group, is celebrating its 25th year as a leading resource for people affected by macular degeneration and similar diseases leading to central vision loss. The organization posted its first annual “Summary of Research and Development” in a June 2006 newsletter to members of its then fledgling International Low Vision Support Group. 

To put the past quarter-century of progress in perspective, this presentation revisits those early headlines and follows each with the most recent information available. The line of breakthroughs and successes has, however, not gone unbroken, so the presentation will also include mention of studies and therapies that were not able to meet expectations. Then, to finish on a positive note, highlights of the exciting field of low vision technology will be shared. 

The most notable development of this past 25 years was FDA approval of a safe and effective treatment for neovascularization, or growth of new blood vessels, which once caused quick and irretrievable central blindness in thousands of people with macular degeneration, diabetic retinopathy, diabetic macular edema, and degenerative myopia.  And that is where this review of headlines begins.

An article in December 2004, titled “Macugen Approved For Treatment of Wet AMD” announced that “a large trial of Macugen (pegaptanib sodium) on 1,196 patients at 117 centers around the world was completed in 2003 and will be available in clinics in 2005. Data showed that Macugen stabilized or improved vision in 33% of the patients in the trials, while the same results occurred in 23% of a control group not given Macugen…”

And a little more than a year later, another headline revealed that “Lucentis Maintained or Improved Vision in Approximately 95% of Patients in [a] Phase III Study.”This was a huge step forward as “Genentech, Inc. announced positive one-year results from its second pivotal Phase III study of their investigational drug Lucentis . . . in patients with wet age-related macular degeneration (AMD).”

Lucentis was approved in 2006 for treatment of wet AMD, far-outpacing Macugen as the standard of care. Since then, it has also been approved for treatment of diabetic retinopathy, diabetic macular edema, myopic choroidal neovascularization, and macular edema following retinal vein occlusion. It is one of four drugs that are now available for treatment of neovascular eye diseases, the others being Macugen (2005), off-label Avastin (2005), Eylea (2011), and Beovu (2019). And with each new product, improvements in extended release up to 12 weeks between injections are indicated.

Science has worked for over 3 decades to find the most effective methods for treating neovascularization in the retina. In the 90’s and into the beginning of the century, two laser surgeries were the only viable options. Thermal coagulation required a hot laser to seal off leaking vessels, and photodynamic therapy incorporated a lower-power laser that activates an injected drug to coagulate leaking vessels when exposed to light. Both laser treatments are still used today, but only if necessary or in combination with drug therapies. 

Taking the place of laser surgery has been development of medication that blocks vascular endothelial growth factor (VEGF), a protein produced by the body that stimulates formation of blood vessels. This “anti-VEGF” therapy goes a step further than just coagulating blood vessels. Injected into the eye, it actually halts the growth of those vessels in the first place.

And then there are combination drug therapies, which are designed to accompany anti-VEGF therapy to improve or prolong results. Most recently, Genentech’s Faricimab has been tested in combination with their anti-VEGF drug Lucentis. Another drug, Alimera Sciences’ Iluvian, a corticosteroid implant, demonstrated effectiveness in the treatment of neovascular diabetic retinopathy, but concerns by the FDA about safety and manufacturing standards have slowed its progress toward clinical trials.

Efforts are also being made to develop methods of automatic sustained release of drugs in the eye. For example, an implant called NT- 501 uses encapsulated cell technology (ECT) to manufacture and secrete a drug into the interior of the eye. In a 2012 study, NT-501 implants produced a chemical consistently over a 2-year period, but trials are currently stalled. The NT-501 is one of three sustained-release implantable drug delivery devices, the others being Retisert and Ozurdex, all of which could someday greatly relieve the burden of frequent injections.

And now new research has shown that some people may not need to undergo injections forever. A study concluded in 2019 suggested that some patients with wet AMD can actually retain good visual acuity with no treatment for at least 3 years after stopping anti-VEGF treatment. Further research may be able to identify characteristics in those patients who demonstrate higher visual acuity after cessation of injections. 

Finally, several other alternatives to a needle in the eye are being considered, such as a port delivery system, oral medications, and eye drop formulations.

With all of the understandable excitement caused by the new anti-VEGF treatments during recent years, news about wet AMD has overshadowed developments in the fight against the dry form of macular degeneration.  Now, however, dry AMD, more specifically in the advanced stage of geographic atrophy (GA) is also making headlines. 

Back in February 2006, an article titled “Statins and AMD” announced that researchers had found high doses of statins (which are cholesterol-lowering medications) to be effective at reducing the number of soft drusen deposits in retinas of people with dry AMD.

Drusen are those cellular waste deposits in the retina that have been associated with AMD. A June 2006 report titled, “Drusen Fragments May Lead to Wet AMD”, discussed whether the components of the deposits cause progression to the advanced form of AMD. After several studies through the years, it is now known that, even though drusen are associated with wet AMD, they do not actually cause it. They are, rather, a result of the disease progression. This is evidenced by attempts at removing the deposits with lasers, which has been successful, but with no resultant improvement in the patient’s condition.

Today, scientists are still in agreement that inflammation is a direct result of cholesterol buildup. They also agree that if inflammation can be reduced with statin drugs, such drugs may turn out to be effective at slowing drusen formation in AMD, treating proliferative vitreoretinal diseases, slowing the loss of acuity in diabetic retinopathy, and reducing the risk of open-angle glaucoma. Since, however, statins may carry unwanted side effects, scientists are weighing those risks with the benefits to the retina, and considering if other anti-inflammatories, such as aspirin, might be just as effective.

Many drugs have been tested for inhibition of the body’s complement system, which is part of the immune system, now widely known to be a principal factor in developing dry AMD. Apellis Pharmaceutical’s APL-2 was the first complement inhibitor tested since 2007 in patients with dry AMD, also called “geographic atrophy”. The company is currently running Phase 3 studies to assess the efficacy and safety of multiple intravitreal injections of APL-2.

Three other clinical trials are also in progress. They are Allergan’s Ozurdex implant containing brimonidine, the University of Virginia’s TOGA study evaluating low dose oral doxycycline, and Genentech’s GALLEGO study evaluating the safety, tolerability, and efficacy of intravitreal injections of a compound assigned the unwieldy name RO7171009.

“No Association Between Cataracts and Macular Degeneration” was the heading of a May 2006 report about analyses of data from the Age Related Eye Disease Study (AREDS) showing “no clear evidence of an association between cataract surgery and neovascular AMD”, and that “most patients undergoing cataract surgery can probably be reassured that surgery will not markedly increase their risk for progression to neovascular AMD”. 

Since that report, most retinal surgeons have agreed that there is minimal danger of retinal complications from such surgery in the hands of experienced practitioners. Most recently, Emily Chew, MD, reported that, after reviewing patient follow-up data from her AREDS research, “The frequency of [wet] AMD, geographic atrophy, and central geographic atrophy did not differ between patients who had cataract surgery and those who did not.”

Also in May 2006, and article titled “New Lutein Findings” contradicted earlier conclusions that the dietary carotenoids lutein and zeaxanthin are protective against the progression of AMD. “The Melbourne Collaborative Cohort Study presented evidence…that neither of the substances are protective against the disease”.

This, however, was countered by an article the very next month titled: “AREDS Formula Revised”. It announced that a second age-related eye disease study was in planning stages to include not only lutein and zeaxanthin, but to lower the amount of zinc, eliminate beta-carotene, and include DHA/Omega 3 (fish oil).

So, in spite of some early conflicting data, lutein and zeaxanthin have replaced beta-carotene in the revised formula, called AREDS-2. Fish oil, however, has not been included. 

The replacement of beta-carotene in the AREDS-2 formula resulted in a smaller decrease in the risk of progression to advanced AMD, but the revised formula is still recommended for people in the intermediate stage. The dosage of zinc has remained the same, but some supplement manufacturers have opted to lower it in their products to address digestive problems experienced by some users.

On another front, a June 2006 article, “Blue Light Risk”, reported research from the University of Chicago confirming that “the blue light wavelength peaking at 440 nanometers causes retinal damage through photochemical change and [programmed] cell death.” 

This research was done with animals’ eyes, but no trials have yet been, and probably won’t be, accomplished to confirm the findings in humans. The opinions, therefore, are split fairly evenly between risk and no-risk, leaving it up to the individual to decide if precautions should be taken.  

A recent surge in marketing for blue-light-filtering lenses has kept the issue alive, particularly in connection with the use of electronic devices with screens. The sun, and full spectrum lamps which imitate the sun, are the two strongest and most common sources of blue light. Blue light intensity from screens is much less than either of those sources, so most experts agree that individuals who are concerned about exposure to digital screens might simply follow sensible practices like limiting screen time, taking periodic breaks, and taking advantage of light-filtering options.

Another May 2006 article announced that “Ocular coherence tomography [is] useful in determining [the] need for Lucentis treatment”, revealing that “a study by the Bascom Palmer Eye Institute, University of Miami, was evaluating the use of optical coherence tomography (OCT) for determining when patients needed an injection of Lucentis . . .”

OCT has since become the gold standard for diagnosing retinal disease, surpassing fluorescein angiography (FA) as the most common diagnostic procedure. And now, ocular coherence tomography angiography (OCTA) has combined both technologies by producing side views of the retinal layers alongside frontal imaging. Like the original OCT, OCTA requires neither dye injections nor uncomfortable camera flashes, so not only are patients happier, but frequent and better imaging is possible, making the doctors’ assessments more precise.

Treatment for wet AMD has indeed been a hot news topic since the early 2000’s, but two therapies have been developing in tandem with that research which could someday make treatment unnecessary. Those are gene replacement therapy and stem cell therapy, both of which could bring a cure for vision impairment and blindness.

A headline in January 2006 declared that “Gene Replacement Therapy [was] Successful in Early Trials.” Researchers at Johns Hopkins University Medical Center used gene replacement therapy to halt, at least temporarily, retinal bleeding in patients with wet AMD. That was done by injecting a PEDF (pigment epithelial derived factor) gene into the eyes of patients during a phase I clinical trial.

That work, and other work like it, led to successful delivery in December 2017 of a normal gene to replace a defective gene in three young patients with Leber congenital amaurosis, leading the way to potential gene replacement therapy for other retinal diseases. In view of the initial success, scientists became enthused about studying how genetic variants play a part in AMD. Retina gene therapy clinical trials are currently testing more than 1,150 patients enrolled at more than 30 sites to determine how AMD genes relate to development of the disease and to look for targets for new treatment strategies.

For example, a preliminary study last October showed that patients with wet AMD had long-term vision stabilization and anatomic improvement following a single injection of RGX-314, an investigational gene therapy.

Three of six study participants showed sustained benefit from a single injection of RGX-314 for more than 1.5 years. And in another cohort with shorter follow-up, nine of 12 patients remained free of rescue medication for up to 6 months.

The excitement caused  by headlines such as “Stem Cells Promise Cure”, back in April 2006, may have been a bit premature. The author wrote, “Stem cell transplantation is showing promise as a potential cure for retinal disease…significant improvement has been noticed in vision of the patients after one month of injecting stem cells. There is further improvement after a gap of three months”. Stem cell replacement may someday soon restore vision after a single visit to the clinic, but there is still much work to be done to ensure a safe outcome. And the work is proceeding.

Results from several clinical trials have added support for the use of human embryonic stem cells as treatment for the dry form of macular degeneration. Stem cells injected into the eye appear to be replacing missing cells damaged by the disease, with no serious side effects, and they are even improving patients’ vision. 

A National Eye Institute (NEI) study will soon test the safety of a stem cell treatment for dry AMD, in which the researchers will take a patient’s own blood cells and convert them into stem cells that can be programmed to become retinal pigment epithelial (RPE) cells, which nourish the photoreceptor sight cells. These RPE cells are then grown in sheets one cell thick on a biodegradable scaffold and inserted into the retina. The expectation is that they will replace and nourish the lost cells and restore sight.

Researchers continue to look for sources of stem cells other than embryos. Newly-discovered sources are bone marrow, brain tissue, umbilical cord blood, amniotic fluid, and even the patients’ own skin and eyelids.

Meanwhile, patients are being warned about companies that are making unsubstantiated claims about stem cell “cures”. At this time, no stem cell treatments for retinal diseases have been approved for clinical use by the FDA, and anyone considering participation in a clinical trial should ask if the FDA has reviewed the treatment. An honest health care provider would be able to confirm this information by providing a New Drug Application (NDA) number and the chance to review the FDA communication approving its experimental use. Patients should ask for this information before getting treatment, even if the stem cells are their own.

These headlines have focused mostly on the positive developments in retinal research. Disappointingly, not all expenditures of time and money have succeeded in bringing better treatments into the clinic. Some famous studies and procedures that have been suspended or cancelled, or that have simply not yielded encouraging results over the past quarter-century, are retinal transplantation, transpupillary thermotherapy, radiation therapy, rheopheresis therapy, and drusen lasering.

Advancement in low vision technology, however, has been nothing less than miraculous for such a relatively brief period of time, with developments such as:

  • Desktop electronic magnifiers (CCTVs) for displaying enlarged and enhanced text onto a screen.
  • Portable hand-held electronic magnifiers, which are essentially small battery-operated versions of CCTVs.
  • Bioptic glasses, which are small binoculars built into the top of prescription glasses allowing for periodic distance viewing while driving.
  • Optical character recognition systems, which can read text and hand writing aloud.
  • Portable way-finding systems for navigating unfamiliar environments outdoors or indoors.
  • Voice operation of computers, smart phones, and appliances
  • Artificial intelligence (AI) applications for identifying the environment and recognizing people.
  • A miniature telescope implanted into one eye, allowing constant hands-free magnification.
  • Head-worn electronic vision enhancement systems for adjustable magnification and improvement of clarity, brightness, and contrast.
  • Currency and color identification devices, available separately or as smart phone applications.
  • Devices for self-monitoring vision changes.
  • Expansion of built-in accessibility features on smart phones and computers providing text enlargement, text-reading, and zoom capabilities.

Finally, the growth of the Internet since the 1990’s has given low vision people unlimited access to the information and support they need to manage their lives successfully. Through such formats as email discussion groups, message boards, social media platforms, webcasts, podcasts, and news blogs, people are sharing and learning to an extent never-before possible.

Sometimes, it seems that things are not moving fast enough toward  treatments and cures. Impatience  is understandable when viewed within the limits of a single lifetime. But when viewed through the wider lens of history, the progress since the turn of this century has been immense and the expansion of knowledge has been exponential.

The ironically-named 2020’s will see the culmination of a great deal of research that first saw light during this past 25 years. The massive amount of work in pharmacology, surgery, and technology will begin to coalesce into treatments, cures, and assistive media leading to a world virtually without blindness. Being on hand to personally witness, and to be a part of this unique time in history, is a privilege for patients and professionals alike. And the honors go to men and women who are continuing to press forward for the benefit of those yet to come.