Researchers Progress Toward Eye Drop for Retinal Disease

Staff
4/2/2014

Drugs used to treat blinding disorders could be successfully administered by eye drops rather than unpleasant and expensive eye injections, according to new research led by University College London scientists that could be a breakthrough for the millions worldwide suffering from age-related macular degeneration and other eye disorders.

One in five people over 75 have AMD. The research findings are significant due to growing patient numbers and an increasing demand for the eye injections that halt the progression of the disease.

The research, demonstrated in animal models and published in nanotechnology journal Small, demonstrates that it is possible to create formulations of tiny nanoparticles loaded with the AMD drug Avastin and deliver significant concentrations to the back of the eye. Lead author Professor Francesca Cordeiro (UCL Institute of Ophthalmology) said: “The development of eye drops that can be safely and effectively used in patients would be a magic bullet—a huge breakthrough in the treatment of AMD and other debilitating eye disorders.

“The current treatment of injecting drugs into the eye is uncomfortable, detested by patients and often needs repeated monthly injections in hospital for as long as 24 consecutive months. It’s impossible to exaggerate the relief patients would feel at not having to experience injections into their eyes.”

Britain’s National Health Service  is currently overburdened with patients who need repeat eye injections and the numbers are set to rise exponentially over the next 10 years. Demand is high, and injections are difficult to administer, time-consuming and very expensive. The treatment also carries a risk of infection and bleeding, increased by the frequency of recurrent injections into the eyes. In the United States, well over 1 million ocular injections were given in 2010. In the UK, 30,500 injections were estimated to have been given in 2008—a 150-fold increase in 10 years.

It was previously thought that drugs used to treat AMD such as Avastin and Lucentis have molecules that are simply too large to be effectively transported in an eye drop. First author Dr. Ben Davis (UCL Institute of Ophthalmology) added: “There is significant interest in the development of minimally invasive systems to deliver large drug molecules across biological barriers, including the cornea of the eye.

“We have shown in experimental models a formulation system to get substances including Avastin across the barriers in the eye and transport them across the cells of the cornea. In theory, you could customize the technology for different drugs such as Lucentis … as it is a smaller molecule than Avastin so likely to be delivered effectively via this method.

“All the components we used are safe and well-established in the field, meaning we could potentially move quite quickly to get the technology into trials in patients—but the timescales are dependent on funding.” The paper includes functional data showing that the Avastin administered stops the blood vessels from leaking and forming new blood vessels.

This technology has been patented by UCL’s technology transfer company UCL Business and the researchers are seeking commercial partners to accelerate development.


Eye May Reveal Early Alzheimer’s

Investigators at the Cedars-Sinai Regenerative Medicine Institute have discovered eye abnormalities that may help reveal features of early-stage Alzheimer’s disease. Using a novel laboratory rat model of Alzheimer’s disease and high-resolution imaging techniques, researchers correlated variations of the eye structure, to identify initial indicators of the disease.

“Detecting changes in the brain that indicate Alzheimer’s disease can be an extremely challenging task,” said Shaomei Wang, MD, PhD, lead author of the study and an associate professor in the Regenerative Medicine Institute and Department of Biomedical Sciences. “By using the eye as a window to brain activity and function, we may be able to diagnose patients sooner and give them more time to prepare for the future. Options may include earlier enrollment in clinical trials, developing support networks and dealing with any financial and legal matters.”

Using both animal models and postmortem human retinas from donors with Alzheimer’s disease, researchers found changes in the retinal pigment epithelial layer and in the thickness of the choroidal layer. Changes in these two regions were detected using sophisticated, state-of-the-art imaging and immunological techniques.

With high-resolution, microscopic imaging and visual acuity measurements, investigators were able to monitor tissue degeneration in the cell layer and vascular layer at the back of the eye, as well as decline in visual function, that were strongly associated with Alzheimer’s disease.

“Greater magnitude in these eye abnormalities may mean a greater chance of a patient having Alzheimer’s disease,” said Alexander Ljubimov, PhD, director of the Eye Program within the Regenerative Medicine Institute and study co-author. “We found that a rat model showed similar signs to the human ailment in the eye. If true in a larger number of humans, these findings may be used to study Alzheimer’s disease mechanisms and test potential drugs.”

Though additional research is needed to investigate the mechanisms of these ocular changes in relation to changes in the brain, investigators hope to ultimately aid early diagnosis of Alzheimer’s disease by studying the most approachable part of the central nervous system: the eye. Cedars-Sinai has been at the cutting edge of studies on the eye and Alzheimer’s disease with a previous report showing amyloid plaques, a hallmark of Alzheimer’s disease, also build up in the eye using a similar animal model of the disease.


Finding in Canine Eye Linked to Retinal Diseases
In humans, the fovea
is critically important to viewing fine details. Densely packed with cone photo receptor cells, it is used while reading, driving and gazing at objects of interest. Some animals have a similar feature in their eyes, but researchers believed that among mammals the fovea was unique to primates—until now.

University of Pennsylvania vision scientists report that dogs, too, have an area of their retina that strongly resembles the human fovea. What’s more, this retinal region is susceptible to genetic blinding diseases in dogs just as it is in humans.

“It’s incredible that in 2014 we can still make an anatomical discovery in a species that we’ve been looking at for the past 20,000 years and that, in addition, this has high clinical relevance to humans,” said William Beltran, an assistant professor of ophthalmology in Penn’s School of Veterinary Medicine and co-lead author of the study with Artur Cideciyan, research professor of ophthalmology in Penn’s Perelman School of Medicine.

“It is absolutely exhilarating to be able to investigate this very specialized and important part of canine central vision that has such unexpectedly strong resemblance to our own retina,” Dr. Cideciyan added.

The paper was published in the journal PLoS ONE.

It is known that dogs have an area centralis, a region around the center of the retina with a relative increase in cone photoreceptor cell density. But dogs lack the pit formation that humans have, and, before this study, it was believed that the increase in cone photoreceptor cell density didn’t come close to matching what is seen in primates. Prior to this study, the highest reported density in dogs was 29,000 cones per square millimeter compared to more than 100,000 cones per square millimeter seen in the human and macaque foveas.

It turns out that previous studies in dogs had missed a miniscule region of increased cell density. In this study, while examining the retina of a dog with a mutation that causes a disease akin to a form of X-linked retinal degeneration in humans, the Penn researchers noticed a thinning of the retinal layer that contains photoreceptor cells.

Zeroing in on this region, they examined retinas of normal dogs using advanced imaging techniques, including confocal scanning laser ophthalmoscopy, optical coherence tomography and two-photon microscopy. By enabling the scientists to visualize different layers of the retina, these techniques allowed them to identify a small area of peak cone density and then estimate cone numbers by counting the cells in this unique area.

Based on their observations, the researchers found that cone densities reached more than 120,000 cells per square millimeter in a never-before-described fovea-like region of the area centralis, a density on par with that of primate foveas.

They also recognized that the “output side” of this cone-dense region corresponded with an area of dense retinal ganglion cells, which transmit signals to the brain.

Human patients with macular degeneration experience a loss of photoreceptor cells at or near the fovea, resulting in a devastating loss of central vision.

To see whether the fovea-like region was similarly affected in dogs, the Penn researchers used the same techniques they had employed to study normal dogs to examine animals that had mutations in two genes (BEST1 and RPGR) that can lead to macular degeneration in humans.

In both cases, the onset of disease affected the fovea-like region in dogs in a very similar way to how the diseases present in humans, with central retinal lesions appearing earlier than lesions in the peripheral retina.

“Why the fovea is susceptible to early disease expression for certain hereditary disorders and why it is spared under other conditions is not known,” Dr. Cideciyan said. “Our findings, which show the canine equivalent of a human genetic disease affecting an area of the retina that is of extreme importance to human vision, are very promising from the human point of view. They could allow for translational research by allowing us to test treatments for human foveal and macular degenerative diseases in dogs.”

The fact that dogs have a fovea-like area of dense photoreceptor cells may also indicate that dogs are seeing more acutely than once suspected.

“This gives us a structural basis to support the idea that dogs might have a higher visual acuity than has been measured so far,” Dr. Beltran said. “It could even be the case that some breeds have an especially high density of cells and could be used as working dogs for particular tasks that require high-level sight function.”


Lifestyle Changes Can Spare Visual Impairment
A physically active lifestyle
and occasional drinking are associated with a reduced risk of developing visual impairment, according to a study published online in March in Ophthalmology.

Visual impairment is associated with a poorer quality of life and, when severe, loss of independence. In 2020, the number of people in the United States with visual impairment is projected to increase to at least 4 million. This is a 70-percent increase from 2000 and is due to the growing aging population and prevalence of age-related eye diseases.

To help determine ways to decrease the growing burden of visual impairment, researchers from the University of Wisconsin School of Medicine and Public Health examined the relationships between the incidence of visual impairment and three modifiable lifestyle behaviors: smoking, drinking alcohol and staying physically active. The research was conducted as part of the Beaver Dam Eye Study, a long-term population-based cohort study from 1988 to 2013 of nearly 5,000 adults aged 43 to 84 years.

The researchers found that over 20 years visual impairment developed in 5.4 percent of the population and varied based on lifestyle behaviors as follows:

•    Physically active persons (regular activity three or more times a week): Over 20 years, 6.7 percent of sedentary persons and 2 percent of physically active persons developed visual impairment. After adjustment for age, these figures show a 58-percent decrease in odds of developing visual impairment in physically active persons compared to those who were sedentary.

•    Occasional drinkers (those who have consumed alcohol in the past year, but reported fewer than one serving in an average week): Over 20 years, 11 percent of non-drinkers (people who have not consumed alcohol within the past year) developed visual impairment while 4.8 percent of occasional drinkers did so. After adjustment for age, these figures show a 49-percent decrease in odds of developing visual impairment in those who were occasional drinkers compared to those who consumed no alcohol.

•    While the odds were higher in heavy drinkers and smokers compared to people who never drank heavily and never smoked, the associations were not statistically significant.

While the study provides risk estimates of associations of lifestyle factors with the incidence of visual impairment, the researchers caution that a limitation to their study is that the findings may be due, in part, to unmeasured factors related to both lifestyle behaviors and development of visual impairment. The data does not prove that these lifestyle behaviors are directly responsible for increased risk.

“While age is usually one of the most strongly associated factors for many eye diseases that cause visual impairment, it is a factor we cannot change,” said Ronald Klein, MD, MPH, lead researcher of the study. “Lifestyle behaviors like smoking, drinking and physical activity, however, can be altered. So, it’s promising, in terms of possible prevention, that these behaviors are associated with developing visual impairment over the long term. However, further research is needed to determine whether modifying these behaviors will in fact lead to a direct reduction in vision loss.”  REVIEW