A new study by scientists from the Schepens Eye Research Institute/Massachusetts Eye and Ear and the Department of Ophthalmology, Harvard Medical School, suggests that ranibizumab, an anti-VEGF-A monoclonal antibody fragment, is a potential prophylaxis for proliferative vitreoretinopathy. The study was published on the American Journal of Pathology website and scheduled for the May 2013 print edition.

PVR, a serious, sight-threatening complication in people recovering from surgical repair of retinal detachment, is difficult to predict, lacks effective treatment options and substantially reduces an individual’s quality of life. Each year 55,000 people are at risk for developing PVR in the United States alone.

“In this manuscript we present basic studies that have clear implications for disease pathogenesis and therapy,” said senior author Andrius Kazlauskas, PhD, senior scientist and Sinon Scholar in Retinal Research at Schepens and a professor of ophthalmology at Harvard Medical School.

Researchers found that the putative mediators of PVR pathogenesis are growth factors, which contribute to common diseases such as atherosclerosis and cancer. “Consequently, elucidating functional relationships between growth factors and resolving their contribution to pathogenesis is of wide interest because such information will substantially advance our ability to combat a broad spectrum of diseases,” Dr. Kazlauskas said.

While investigating the functional relationships between growth factors known to promote pervasive human diseases, researchers discovered that ranibizumab reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing this disease.

These pre-clinical findings suggest that one of the clinically approved approaches to neutralize VEGF-A constitutes a novel prophylactic for an incurable, blinding disease.

“Our discoveries also raise the provocative idea that anti-VEGF-based therapies may be effective for managing more than the angiogenesis—and vascular-permeability-driven pathological conditions,” Dr. Kazlauskas says.

B+L’s Once-Daily Prolensa Approved for Post-Cataract Care
    The Food and Drug Administration has approved Bausch + Lomb’s New Drug Application for Prolensa (bromfenac ophthalmic solution) 0.07 % prescription eye drop, a once-daily nonsteroidal anti-inflammatory drug for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract surgery. Prolensa will be available in 1.6 ml and 3 ml bottle sizes.
     With the potency of the bromfenac molecule in a formulation designed to facilitate ocular penetration, Prolensa’s formulation allows for a lower concentration of bromfenac in a once-daily dosing regimen, B + L says. Prolensa is a solution that does not require shaking to deliver a consistent dose in each drop.
     The efficacy of Prolensa was evaluated in two randomized, double-masked, vehicle-controlled studies of patients undergoing cataract surgery. Each patient received Prolensa or vehicle starting with one drop into the surgical eye on the day prior to and the day of surgery, and for 14 days following surgery. The primary efficacy endpoint was complete clearing of ocular inflammation (assessed by the summed ocular inflammation score, SOIS, which includes cells and flare) by day 15. The secondary efficacy endpoint was the number of subjects who were pain-free on day one after surgery.
     Results from the pivotal studies demonstrated Prolensa to be superior to vehicle in the treatment of both inflammation and pain following cataract surgery. Twice as many patients as vehicle (46 percent versus 20 percent) demonstrated complete clearance of inflammation (SOIS of 0) at day 15. The difference in the average postoperative inflammation severity between the treatment and vehicle arms was statistically and clinically significant by day eight. Nearly four of five patients treated with Prolensa were pain-free at day one (78.8 percent versus 49.5 percent for vehicle; p<0.0001). Patients treated with Prolensa reported a lower incidence of foreign body sensation and photophobia and had less redness than those treated with vehicle. For information, visit bausch.com.
Swedish Research Targets CNS for Eye Diseases
Using new technology and new approaches, researchers at Lund University in Sweden hope to be able to explain why people suffer vision loss in eye diseases such as retinal detachment and glaucoma.

Research on diseases of the eye such as retinal detachment and glaucoma has until now focused on the biochemical process that takes place in the eye in connection with the diseases.

Fredrik Ghosh, MD, PhD, and Linnéa Taylor have concentrated instead on attempting to understand what happens on a biomechanical level in the diseases and have produced results that have drawn a lot of interest from experts.

“We have not previously understood the mechanisms behind glaucoma and retinal detachment, but we knew that these diseases had a strong mechanical component. Our findings could form an initial explanation as to why we develop these diseases,” said Dr. Ghosh and Ms. Taylor.

Using new technology, the eye researchers at the Department of Clinical Sciences in Lund, in collaboration with researchers at the Department of Biology at Lund University, have developed a method to investigate the importance of the biomechanical environment within the central nervous system.

For their studies, they grow retinal tissue from adult pigs in a stretched state similar to the normal mechanical state present in the living eye. Compared with unstretched tissue, which in cultures dies after a few days when the retina’s mechanical balance is disturbed, studies can now be performed for up to 10 days in retina with a well-preserved structure and significantly higher cell survival.

“This gives us new tools to understand in a more concrete manner how biomechanical factors in the central nervous system influence the health of cells when we are healthy and when we suffer from diseases. This will not only have major importance for our understanding of how diseases come about in the central nervous system, but also for future disease treatment,” said the researchers.

The central nervous system, which includes the brain, spinal cord and retinas, is a complicated organ, especially in terms of structure. The entire system is under the mechanical influence of fluid pressure, among other factors. The new data from the group in Lund indicates that when the biomechanical balance is disturbed, as happens in retinal detachment and glaucoma, the normal function of the retina is lost, resulting in serious sight impairment or blindness.

Cholesterol Tied to Macular Disease
A study published on April 2nd in the journal Cell Metabolism sheds light on how cholesterol metabolism in white blood cells—called macrophages—contributes to macular degeneration and proposes new drugs, some ad-ministered via eye drops, to cure the disease in mice. 
“Our increased understanding of cholesterol’s role in the growth of ocular blood vessels helped us identify therapeutically modifiable pathways, opening up avenues for new treatments that may help us prevent blindness caused by macular degeneration,” says senior study author Rajendra Apte MD, PhD, of Washington University School of Medicine.

Past studies have shown that macrophage cholesterol accumulation is a common feature in AMD. In addition, macrophages promote the abnormal growth of blood vessels in the aged eye, leading to blindness. But until now, the precise mechanisms by which macrophages cause the growth of new blood vessels and potentially blindness, as well as the possible role of cholesterol metabolism in this process, were not known.

In the new study, Dr. Apte and his team found that macrophages taken from both old mice and human AMD patients had low levels of ABCA1, a cholesterol transporter known to move cholesterol out of the cells. As a result, these old macrophages accumulated high levels of cholesterol and were unable to inhibit the growth of new blood vessels. In order to restore cholesterol transport, the researchers focused on two key cholesterol regulators: Liver X Receptor (LXR), whose activation is known to promote cholesterol efflux, and microRNAs-33, which has been shown to directly decrease ABCA1 expression. Old mice were treated with either an LXR agonist, delivered via eye drops or injection, or a microRNA-33 inhibitor. Both of these drugs increased ABCA1 protein levels and improved cholesterol transport in macrophages, resulting in a reduction in the growth of blood vessels. Because the LXR agonist can be delivered with eye drops, it could potentially cause fewer side effects.

“Abnormal blood vessel growth is a characteristic of not only AMD, but also diverse disease processes outside the eye, including cancers and atherosclerosis, which are both associated with significant morbidity and mortality,” Dr. Apte says. “Our findings may have significant relevance in our understanding of the pathobiology of these conditions.”

EyeGate: Uveitis Treatment as Good As Eye Drops
EyeGate Pharma announced that the topline results from its Phase III study of EGP-437, a corticosteroid formulation, in anterior uveitis pa-tients demonstrate that two ionto-phoretic treatments of EGP-437 achieved the same response rate as the positive control, prednisolone acetate 1% ophthalmic suspension administered as multiple daily eye drops, the current standard of care.

In this randomized, double-masked placebo-controlled study conducted at 45 clinical sites in the United States, a total of 193 patients were randomly assigned into one of two treatment arms (iontophoretic treatment on days 0 and 7 or 14 days daily treatment of prednisolone acetate 1% ophthalmic solution, which was followed by two weeks of standard tapering). The primary efficacy endpoint is the proportion of patients with anterior chamber cell count of zero on day 14, which is defined as a complete response.

In all randomized subjects (the intent-to-treat population), only two iontophoretic treatments with EGP-437 (days 0 and 7) resulted in 32 complete responses out of 96 patients on day 14; the standard-of-care uveitis treatment (daily treatment), prednisolone acetate 1% ophthalmic suspension, also yielded 32 complete responses out of 97 patients who received multiple daily self-administered eye drops over the first 14 days (days one to seven: eight drops per day and days eight to 14: six drops per day).

The incidence and severity of treatment-emergent adverse events in both groups were comparable; there were fewer incidences of elevated intraocular pressure in the EGP-437 group.

“Inadequate compliance with aggressive eye drop regimens often leads to treatment failures,” said Dr. John Sheppard, the study’s principal investigator. “Offering our uveitis patients a safe, effective treatment option that is controlled by the health-care provider rather than the patient represents an important breakthrough, especially when there is a history of poor compliance, difficulty with eye drop self-administration, elevated IOP, glaucoma or preservative toxicity. Iontophoresis technology creates new paradigms for both ocular drug delivery and for uveitis management.”  REVIEW