July/August 2007 News
CLINICAL NEWS

Current DR Screening Not Cost Effective
Researchers from the Yale University School of Medicine found that the standard of screening youth (aged ≤21 years) with type 1 diabetes for retinopathy is not cost effective or necessary for patients who maintain strict glycemic control with intensive insulin therapy.

Although the America Diabetes Association recommends screening for diabetic retinopathy (DR) in children who have presented with diabetes for 3 to 5 years, the recommendation is not needed in an era when A1C [levels] are much lower, according to the authors.

“This recommendation may have been appropriate in the preintensive-treatment era when elevated A1Cs were associated with early development of DR,” the authors wrote in Diabetes Care. “Results of the Diabetes Control and Complications Trial (DCCT), however, demonstrated that intensive treatment in adolescents markedly delayed early microvascular changes in the retina.”

Additionally, many pediatric diabetes clinics do not use advanced techniques to perform most routine eye screening, reducing the likelihood of identifying early retinal changes, the authors wrote.

“There was a very low yield from the DR exams, due in large part to the low A1C levels achieved by our patients,” the investigators said. Pursuing early identification and treatment of hypertension and microalbuminuria to prevent clinical nephropathy and macrovascular disease is recommended.

The investigators calculated a cost of $200 for every new patient visit and $175 for each follow-up visit. These costs did not take into account expenses for transportation or time lost from work and school. Screening would be more cost effective if it was limited to patients with elevated levels of A1C, hypertension, and microalbuminuria, they said. “These all involve assessments that can be carried out during regular diabetes clinic visits and do not require extra days being lost from work or school,” the authors concluded.

Pupil Size an Indicator of Retinal Deterioration
Pupil abnormalities may be an early indicator for future microvascular disease, including deterioration of the retina and retinopathy, according to data from a 12-year follow-up study.

Ann M. Maguire, MB, BOA, BCh, and colleagues from The Children’s Hospital at Westmead, in Sydney, Australia, examined the correlation between baseline pupillometry tests, the presence of microalbuminuria, and retinopathy in 335 youths with type 1 diabetes. All participants originally underwent cardiovascular testing in the early 1990s.

Researchers found that during follow-up, 10% had severe retinopathy that required laser therapy, 15% had moderate retinopathy, 44% showed signs of mild retinopathy, and 31% had no retinopathy.

Baseline cardiovascular tests in the lower quartile were not associated with retinopathy or microalbuminuria, according to the authors. Resting pupil diameter in the lower quartile (eg, <4.7 mm) and A1C levels at baseline, however, were significant predictors for retinopathy.

“While the relationship between cardiac autonomic neuropathy and microalbuminuria has been described in cross-sectional studies … our longitudinal study using pupillometry also extends these findings to retinopathy. Our results support the idea that the changes in vascular tone cause damage in addition to coexisting glycemic damage. Although pupillometry assessment was not performed in the DCCT, it is clear from the DCCT that neuropathy progression can be prevented by improving glycemic control,” the authors wrote. “The effect of improved glycemic control on early pupillometry abnormalities, therefore, needs to be ascertained. In the meantime, it would be prudent to consider these patients at higher risk of developing microalbuminuria and retinopathy.”

Scientists Analyze Proteins in Retinal Cells’ Cilia
By identifying the approximately 2,000 proteins that make up the cilia of photoreceptor sensory cells in mice, researchers at the University of Pennsylvania School of Medicine in Philadelphia have taken the first steps toward curing several inherited eye diseases. The investigators hope to gain a clearer understanding of what goes wrong at the most basic level in diseases that cause blindness and other disorders.

Lead author and research assistant professor Qin Liu, MD, PhD, and Eric A. Pierce, MD, PhD, collaborated with a team of researchers, to perform the analysis for this study. They used mass spectrometry to identify and measure the amounts of proteins in mouse photoreceptor sensory cilia, which senses light in the retina.

“We want to understand how cilia work normally and how their function is disrupted in disease, because their dysfunction is such an important cause of disease,” said Dr. Pierce, Associate Professor of Ophthalmology at the University of Pennsylvania. “One of the first steps to achieve this is to put together a complete list of the parts. Now that we have that, we can figure out how all 2,000 proteins we have identified fit together correctly.”

Dr. Pierce is a pediatric ophthalmologist who specializes in caring for children with retinal degenerations. Approximately half of his patients with degenerative eye diseases have a type of disease that can be identified according to its genetic mutation, he said. He believes that this research will help identify the genetic causes behind the other half of his patient’s conditions.

“We’re narrowing the field,” said Dr. Pierce. “ This research in and of itself cannot find a cure, but it is a great start because it tells us what proteins to study.”

The results appeared in Molecular & Cellular Proteomics.

Insulin Therapy May Treat Early DR
Researchers presented study results at the Association for Research in Vision and Ophthalmology (ARVO), in Fort Lauderdale, Fla., indicating that subconjunctivally delivered insulin ameliorates degenerative and inflammatory responses in the retinas of diabetic rats.

Lead researcher Ravi S.J. Singh, MD, of the Pennsylvania State College of Medicine, in Hershey, Pa., reported that low-dose periocular delivery of insulin to the retina of diabetic rats does not alter blood glucose levels and may treat early diabetic retinopathy, according to an ARVO news release.

Regular human insulin in doses ranging from 0.01 U to 1 U was injected subconjunctivally in control and 1-month-old diabetic male rats. The biological effects of subconjunctival insulin on the retina were analyzed using immunoblotting, kinase assays, and immunohistochemical analysis. Additionally, insulin-loaded hydrogels were designed for subconjunctival implantation to provide low levels of insulin to the retina for prolonged periods. The hydrogels were engineered to be thermoresponsive and hydrolytically degradable.

Pharmacokinetic and pharmacodynamic properties were studied in vitro and in vivo using R28 cells in culture and rats, respectively.

Adult Stem Cells Control Angiogenesis
A team of researchers from the Scripps Research Institute is using adult bone marrow stem cells to form new blood vessels in the eye and to deliver chemicals that will prevent the abnormal formation of new vessels.

This technique, which involved injecting the stem cells into the eye, could potentially be used to stimulate vessel growth and address inherited degenerations of the retina, as well as to treat ocular disease resulting from abnormal retinal angiogenesis.

“We have shown that the cells can incorporate into the degenerating vasculature and make it normal,” said Martin Friedlander, MD, PhD, Associate Professor in the Department of Cell Biology and Chief of the Retina Service in the Division of Ophthalmology, Department of Surgery at Scripps Clinic.

Dr. Friedlander and researchers targeted the activated astrocytes with the stem cell in vivo in mice. In the ocular disease models, the stem cells differentiated into endothelial cells and proliferated, forming new blood vessels. Researchers also found that they could shut down the angiogenesis by first transfecting the stem cells with an angiogenesis inhibitor, human protein tryptophanyl-tRNA synthetase (T2-TrpRS).

These transfected stem cells were also guided by the retinal astrocytes to the vasculature in the back of the eye where they expressed the T2-TrpRS protein and prevented the development of new retinal blood vessels without affecting already established blood vessels.

Triple Therapy Could Improve AMD
Combining injections of bevacizumab (Avastin; Genentech, San Francisco) and triamcinolone with a single session of photodynamic therapy (PDT) could stabilize or improve vision in patients with neovascular age-related macular degeneration (AMD).

According to a study published online in BioMed Central Ophthalmology, 17 eyes with neovascular AMD were treated with PDT once. Forty-eight hours later, patients were injected intraocularly with bevacizumab and triamcinolone. Study authors wanted to test the theory that this treatment combination would interrupt the pathways leading to AMD.

Results showed significant improvements in most eyes at both 12 and 24 weeks. Of 17 eyes, 11 showed improvement in vision and six had no improvement at 12 weeks. At 24 weeks, vision was improved in 13 eyes, and only four eyes remained unchanged.

A larger study has been planned to confirm these results.

Inflammation Marker of AMD in Women
Inflammation may play a role in the development of AMD in women, according to a report published in the Archives of Ophthalmology.

Researchers measured high-sensivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and fibrinogen levels in baseline plasma samples taken from 27,687 patients in the Women’s Health Study. All patients were initially free of AMD and had a mean age of 54.6 years.

One hundred-fifty AMD cases were ascertained, with vision loss of 20/30 or worse by self-report in those affected during the follow-up (mean 10 years).

After adjusting for risk factors, researchers found that elevated circulating levels of hsCRP, sICAM-1, and fibrinogen precede the development of visually significant AMD in women.

Cancer Drug Improves Vision in Radiation Patients
Intravitreal bevacizumab prevents vision loss in patients undergoing radiation therapy, according to research published in the Archives of Ophthalmology.

Paul T. Finger, MD, and Kimberly J. Chin, OD, from The New York Eye Cancer Center, New York, NY, examined six patients who had received plaque radiation therapy for choroidal melanoma. The patients presented with vision loss or distortion from radiation retinopathy (ie, retinal edema, hemorrhages, microangiopathy, and neovascularization).

Treatment involved injections of intravitreal bevacizumab (1.25 mg in 0.05 mL) every 6 to 8 weeks. Progressive reductions in retinal hemorrhages, exudates, cotton-wool spots, and microangiopathy were noted after just one or two injections, authors said. A reduction in macular retinal edema was the most common finding and improvement or stabilization of visual acuity was noted in all cases after 3 months.

There were no bevacizumab-related ocular or systemic adverse effects.

The authors called for more studies of anti-VEGF therapy for radiation retinopathy and optic neuropathy.

INDUSTRY AND BUSINESS NEWS

Helen Keller Award Winner Announced
Allergen, Inc. (Irvine, CA) and its Chairman and CEO, David E.I. Pyott, have been awarded the Helen Keller Global Legacy Award.

“It is Helen Keller International’s [HKI] privilege to recognize David E.I. Pyott for his personal and corporate commitment to the global legacy of Helen Keller,” said Kathy Spahn, HKI’s President and CEO. “Allergen has contributed significant philanthropic support to our worldwide efforts, and has lent its considerable expertise by retaining a seat on the HKI Board of Trustees.”

“The relationship between Allergen and [HKI] exemplifies the positive impact advocacy and industry partnerships can have on the global community,” said Mr. Pyott in a news release. “We are proud to support Helen Keller International in their charitable efforts, and Allergan will continue to deliver on our commitment to eye care through the research and development or innovative ophthalmic products to meet medical needs.”

In its 91st year, the HKI works actively in 22 nations in Africa, Asia, and the Americas, providing achievable solutions that save the sight and lives of the vulnerable and disadvantaged, according to the company.

Avastin Approved for Reimbursement in Italy
The National Health Service (NHS) in Italy will now reimburse for an off-label drug used in the treatment of exudative maculopathy and neovascular glaucoma. According to the recent decision, doctors using bevacizumab (Avastin; Genentech, San Francisco) will now be fully reimbursed by the NHS. The two anti-VEGF) agents pegaptanib (Macugen; OSI/Pfizer, both in New York, NY) and ranibizumab (Lucentis, Genentech) have not been approved for NHS reimbursement.

For that reason, the NHS decision has caused some controversy, especially because unlike pegaptanib and ranibizumab, bevacizumab has not been subjected to clinical trials and is an off-label use.

Matteo Piovella, MD, Director of the Centro di Microchirurgia Ambulatoriale, in Monza, Italy, said that the Italian Society of Ophthalmology (SOI) called for the reimbursement after judging the experiential evidence of bevacizumab as a treatment for maculopathy. “Many of the most important global opinion leaders have more than 4 years of successful experience with this drug for intraocular therapy. It is well tested and well documented that this treatment works.” Dr. Piovella is a member of the editorial board of Cataract and Refractive Surgery Today Europe, Retina Today’s sister publication.

Although bevacizumab is already less expensive than other extremely similar drugs, its low price was not the main motivator for the NHS initiative, Dr. Piovella said in a telephone interview with Retina Today.

“Though this is a bonus, this was not the real motivation to use this drug. What it comes down to for those pushing the approval is that there is plenty of documentation and experience already using this drug, with convincing results.

“I do admit, however, that in the case of a social disease, like age-related maculopathy, the price of therapy is important to consider for one reason. We want to ensure that all patients can receive treatment, and avoid the type of draconian solution that is found in places like England and Wales, where just one in five patients will be offered treatment, but only after they have gone blind in one eye. Without this approval, it is much more difficult for patients to afford this therapy.”

Because of the risk of complications for an intravitreal therapy, the SOI has issued guidelines for using bevacizumab, which include ways to avoid endophthalmitis and decentration.

Dr. Piovella hopes that the reimbursement for bevacizumab will someday be coupled by its approval as a treatment. “There is enough data without the approval for us to be comfortable in using it in patients, but I think it is also important and necessary for the company to start taking steps to achieve approval through the appropriate regulatory entities.”

Drug Delivery System Development Funded by Merck
SurModics, Inc. (Irvine, CA), a provider of surface modification and drug-delivery technologies to the health care industry, announced the signing of a new broad-based license and research collaboration agreement with Merck & Co., Inc. (Whitehouse Station, NJ).

The licensing agreement applies to the I-vation TA drug delivery system, which is used to treat AMD and diabetic macular edema by delivering triamcinolone acetonide to the back of the eye on a sustained-release basis. The drug is implanted during a minimally invasive procedure and may be removed once the drug has been fully released, according to the company.

Merck will lead and fund the development and commercialization activities, as well as give SurModics a $20-million licensing fee. SurModics will also receive up to an additional $288 million in fees and development milestones, as well as royalties on product sales, according to the release.

FDA Approves 3D OCT
The US Food and Drug Administration approved the 3D OCT-1000 from Topcon Medical Systems (Paramus, NJ), as the first Fourier-domain optical coherence tomography (OCT) combined with a color nonmydriatic retinal camera, according to a company news release.

This product provides high-resolution cross-sectional imaging of the retina, aiding in the diagnosis and monitoring a variety of pathologies (eg, retinal detachments, macular holes, AMD, glaucoma). It features a three-dimensional view of the mapped area and accurate pinpoint retinal registrations of the OCT and fundus image.

“The Topcon 3D OCT overcomes several problems encountered with conventional time-domain OCT systems,” said Alexander Walsh, MD, Assistant Professor of Ophthalmology at the Doheny Eye Institute. “Time domain OCT measures less than 5% of a mapped area, while the Topcon 3D OCT measures 100%. With time domain instruments, errors are propagated across a large area, and the instrument may miss small lesions that fall between the lines. By offering a greater number of scans over a large area, the three-dimensional data provide better delineation of pathology and accurate retinal registration and color fundus images, enabling a more precise comparison of OCT data between patient visits. It also allows the practitioner to map the exact location of retinal abnormalities, many of which cannot even be seen with time domain OCT, and enhances visualization for the purpose of patient education. As an investigative site, we have been using the Topcon 3D OCT-1000 for a number of months, and it has provided a significant advantage over time domain OCT,” Dr. Walsh said.

For more information visit Topcon Medical Systems at www.topconmedical.com/3doct.

New Molecule Trial Underway
Othera Pharmaceuticals (Exton, PA) and the National Eye Institute (NEI) announced that an open-label clinical study of OT-551 in patients with bilateral geographic atrophy (GA) has reached its enrollment of 10 patients. OT-551 is Othera’s lead small molecule topical eye drop currently in development for treating the dry and wet forms of AMD and cataracts. OT-551 could represent the first effective treatment for GA, a chronic, degenerative disease affecting approximately 1 million elderly Americans.

Previous studies by the NEI demonstrate patients with bilaterial GA are at significantly elevated risk of experiencing rapid, debilitating vision loss as a result of either continued progression of non-neovascular AMD, or conversion to neovascular AMD. Patients in the NEI-sponsored study are receiving OT-551 eye drops three times per day for 24 months. The study is designed to evaluate OT-551’s potential to reduce the loss in central visual acuity and to slow enlargement of the atrophic area in the macula.

“Results from this study will be among the first to indicate the potential role of OT-551 in treating the progressive damage to the retina and irreversible vision loss associated with GA,” said Al Reaves, PhD, Senior Vice President of Clinical Development with Othera.

OT-551 is a small molecule that acts through multiple pathways to downregulate the disease-induced overexpression of nuclear factor kappa beta, a key player in human inflammatory disease, and to reduce oxidative stress. In preclinical models, OT-551 has demonstrated antioxidative, anti-inflammatory, and antiangiogenic activity, which supports development in diseases of the eye, such as AMD and cataracts.

DNA Used to Correct Vision Deficit
DNA nanoparticles created by Copernicus Therapeutic Inc. (Cleveland) were used to correct vision defects in a mouse model of retinitis pigmentosa (RP), said a research team at the University of Oklahoma Health Sciences Center, led by Muna Naash, PhD, Professor of Cell Biology.

Mutations in genes important in the biology of vision cause RP in nearly 70,000 patients in the United States.

These results demonstrate that “delivery of normal copies of genes into photoreceptor cells can correct vision defects in RP,” said Mark Cooper, MD, Senior Vice President of Science and Medical Affairs at Copernicus Therapeutics Inc. “In addition to the promise of providing corrective therapy for genetic disease such as RP, nucleic acid nanoparticles may also offer the potential to provide effective treatments for more complex disorders (eg, DR, AMD, various diseases that injure ganglion cells and the optic nerve).”

Gene therapy holds great potential for treating and possibly curing a variety of vision-robbing retinal degenerative diseases, said Stephen Rose, PhD, Chief Research Officer of the Foundation Fighting Blindness. “Dr. Naash and Copernicus are demonstrating that nanoparticles show excellent potential for safely and effectively delivering therapeutic genes to the retina.”

The work was funded in part by the Foundation Fighting Blindness. For more information visit www.cgsys.com or www.fightblindness.org.