A large genetic study of age-related macular degeneration has identified three new genes associated with this blinding eye disease—two involved in the cholesterol pathway. Results of this large-scale collaborative study, supported by the National Eye Institute, were published online April 12 in the Proceedings of the National Academy of Sciences.
"Genome-wide association studies require large numbers of patients to discover significant genetic associations. The success of this effort was made possible by a community-wide scientific collaboration of sharing DNA samples and analyzing the genomes of more than 18,000 people," said Paul A. Sieving, MD, PhD, NEI director. "This study increases our understanding of DNA variations that predict individual risks of AMD and provides clues for developing effective therapies."
AMD is a leading cause of visual impairment and blindness in older Americans. Researchers have previously discovered genes that account for a significant portion of AMD risk through genome-wide association studies (GWAS), which scan the entire DNA of individuals to uncover genetic variations related to certain diseases.
The recent large GWAS was led by Anand Swaroop, PhD, currently chief of the NEI Neurobiology-Neurodegeneration and Repair Laboratory, and Goncalo Abecasis, D.Phil., professor of biostatistics at the
The strongest AMD genetic association found in the study was in a region on chromosome 22, near a gene called metalloproteinase inhibitor 3 (TIMP3). Mutations in the TIMP3 gene were previously found to cause Sorsby's fundus dystrophy, a rare, inherited, early-onset form of macular degeneration. Although further research is needed, it is likely that the genetic region pinpointed influences the expression of TIMP3.
The study has also shed light on a new biological pathway for AMD disease development, by uncovering two genes associated with AMD risk in the high-density lipoprotein (HDL) cholesterol pathway: human hepatic lipase (LIPC) and cholesterol ester transfer protein (CETP). Scientists identified two additional genes, lipoprotein lipase (LPL) and ATP binding cassette transporter 1 (ABCA1), that may be involved in the cholesterol pathway as well, but more research is needed to confirm these findings.
HDLs are among a family of lipoproteins that transport essential fats, such as cholesterol, through the bloodstream. It is believed that early stages of AMD are affected by accumulation of oxidation products of cholesterol and other lipids in the retinal pigment epithelium, a layer of cells in the back of the eye. However, the relationship between HDL cholesterol levels in the blood and AMD is still unclear.
"We suspect that these genetic variations found in the cholesterol pathway impact the retina differently from the circulatory system, so cholesterol levels in the blood may not provide meaningful information about AMD risk," Swaroop explained. "Nonetheless, we have uncovered a major biochemical pathway that may be a target for future AMD treatments."
Drug May Offer New Treatment Option for DME
Early-stage human clinical trials showed that a new topical drug was safe and had biological effect, and may offer researchers a new approach to prevent and treat diabetic macular edema.
Researchers at the Wilmer Eye Institute of Johns Hopkins University School of Medicine completed a multicenter human clinical trial treating diabetic macular edema with mecamylamine, a topical drug developed by the
In the Johns Hopkins study, participants with diabetic macular edema were asked to give themselves mecamylamine eye drops twice a day for 16 weeks. (Preclinical research with diabetic mice showed that mecamylamine had the ability to stop the process that contributed to the development and progression of diabetic macular edema.) Based on these preclinical results, the researchers at
At the conclusion of this study, approximately 40 percent of the participants showed significant improvement in overall vision and/or the thickness of the retina. The treatment also showed biological effects in the retina indicating that the drug was able to gain access to the retinal vessels after topical application to the eye. Peter Campochiaro, MD, professor of ophthalmology at the Johns Hopkins University School of Medicine was principal investigator of the study.
In the study participants, approximately 40 percent showed no change, and about 20 percent developed worsening of the condition. The variation in response to the treatment supports the observation that drugs and therapies have less than a 100-percent response rate, likely due to genetic make-up or unknown factors about the disease. These results also emphasize the notion that multiple treatment options for diabetic macular edema must be explored to complement current research in this field.
"The safety and early signals of treatment effect arising from this study may create a strong interest in the development of multiple treatment options that are affordable and can be self-administered, helping to ease the burden of health-care delivery and compliance," said Barbara Araneo, director of complications research for JDRF.
Study Confirms Early Treatment Benefit for ROP
Scientists have shown that through an eye exam, doctors can identify infants who are most likely to benefit from early treatment for retinopathy of prematurity, resulting in better vision for many children. These long-term results of the Early Treatment for Retinopathy of Prematurity (ETROP) study confirm that the visual benefit of early treatment for selected infants continues through 6 years of age. The research was published April 12 online in Archives of Ophthalmology and was supported by the NEI.
"This study has set the standard of care for infants with ROP by showing that early treatment of selected high-risk premature babies has positive longer-term results on vision," said NEI Director Paul A. Sieving, MD, PhD.
An estimated 15,000 premature infants born each year in the
This disease, which usually develops in both eyes, is one of the most common causes of vision loss in children. About 90 percent of infants with ROP have a mild form that does not require treatment, but those who have a more severe form can develop lifelong visual impairment, and possibly blindness.
During pregnancy, the blood vessels of the eye gradually grow to supply oxygen and essential nutrients to the light-sensitive retina. If a baby is born prematurely, growth of the blood vessels may stop before they reach the edge of the retina. In these newborns, abnormal, fragile blood vessels and retinal tissue may develop at the edges of the normal tissue. The abnormal vessels can bleed, resulting in scars that pull on the retina. The main cause of visual impairment and blindness in ROP is retinal detachment. Laser therapy or cryotherapy, using freezing temperatures, are the most effective treatments to slow or stop the growth of abnormal blood vessels.
"The long-term study has given clinicians evidence that infants with ROP should be treated with different strategies based on an infant's risk for a severe form of the disease, which can be determined through an exam at the bedside," said study chair William V. Good, MD, of Smith-Kettlewell Eye Research Institute in San Francisco.
Previously, doctors treated infants with ROP when they estimated their risk for retinal detachment to be 50 percent, a strategy developed through the NEI-supported Cryotherapy for Retinopathy of Prematurity study. Although this was a major finding, many infants still went on to develop severe eye disease. Therefore, the first phase of the ETROP study aimed to discover if doctors could identify infants at a higher risk for progression of the disease and intervene early to improve their vision.
In 2003, the ETROP study found that early treatment—upon diagnosis as higher risk for severe ROP—improved the vision and retinal health of certain infants after nine months.
These infants had dilated or twisted blood vessels in the retina and substantial growth of new blood vessels, classified as Type 1 disease. Eyes with Type 2 ROP, or a more moderate amount of new blood vessel growth, did not benefit from early treatment. Doctors could predict which infants were more likely to benefit from early treatment by identifying certain eye characteristics, such as the appearance and location of the blood vessels.
The current study followed the same 370 children through 6 years of age, when researchers checked their vision and examined the development of their eyes. The nine-month study recommendations were confirmed through six years. Type 1 eyes benefitted from early treatment, and Type 2 eyes had similar results with either early treatment or treatment at the standard time. Seventy-five percent of the early-treated Type 1 eyes were spared legal blindness, compared with 67 percent of Type 1 eyes that received treatment at the standard time. Of the Type 2 eyes that were carefully monitored for disease progression through the standard protocol, more than half improved without treatment.
"Unfortunately, not all eyes selected for early treatment do well," said Robert J. Hardy, PhD, director of the ETROP study coordinating center and professor of biostatistics at the University of Texas School of Public Health in Houston. "Additional research is needed to identify still better methods for the prevention and treatment of severe ROP."
Alcon/Sirion Deal Finalized
Alcon received regulatory approval and finalized the acquisition of the rights in the
Alcon will immediately assume all marketing, promotion and sales of Durezol. Management said that it is continuing to evaluate options to acquire Zirgan, an antiviral recently approved by the Food and Drug Administration for the treatment of acute herpetic keratitis. Durezol emulsion is a topical ophthalmic corticosteroid used to treat postoperative inflammation and pain associated with ocular surgery and received approval from the FDA in 2008. Currently under clinical investigation to treat dry eye and other ocular surface diseases, Zyclorin is a topical ophthalmic immunomodulator and immunosuppressive agent.
