Sight restored with artificial cornea

When natural transplants fail, ophthalmologists turn to corneas made from polymers.

Sixteen years ago, when Awilda Irizarry was 33, glaucoma was diagnosed in her right eye. Over the years, her vision grew increasingly blurry and the pain became agonizing. Her doctor prescribed eyedrops to reduce pressure on her optic nerve; finally, however, the pain was so unbearable that Irizarry had her eye removed.

The pain on the right side was relieved, but Irizarry began to feel pain and lose peripheral vision in her left eye. She had four surgeries, including two donor cornea transplants, but still her vision dimmed and the pain worsened.

“She doesn’t like people to help her much,” said Irizarry’s daughter, Maggie Morales. “She loves being independent, but she was frustrated losing her vision little by little. It got to the point where she was basically blind.”

Last August, just as Irizarry’s doctors were running out of options, Jimmy K. Lee, M.D., joined Yale as the new director of the cornea and refractive surgery sections at the Yale Eye Center. Lee, who had just completed a fellowship at the Wilmer Eye Institute at Johns Hopkins Hospital in Baltimore, came with a clinical interest in corneal transplantation, including artificial corneas. After hearing Irizarry’s case history, Lee thought Irizarry would be an ideal candidate for an artificial cornea transplant. “The main indication for an artificial cornea is when patients have had multiple failed natural cornea transplants,” Lee said. “The immune rejection rate is much lower because the center is an artificial implant.”

The first artificial cornea implant was performed less than 20 years ago, after the device was approved for use in the United States in 1992. “It was uncomfortable for the patient, and there were complications,” said Lee, one of a handful of surgeons in the country who perform artificial cornea transplants. The model Lee uses is the Boston K-Pro (also known as the Dohlman-Doane) developed at Harvard and Massachusetts Eye and Ear Infirmary in the 1960s by Claes H. Dohlman, M.D., Ph.D., con0sidered the founder of modern corneal science. The K-Pro is made of a transparent polymer that offers a visual field almost as wide as that of a normal cornea—the transparent part of the eye that covers the iris, pupil, and anterior chamber and contributes to the eye’s focusing power. A donor cornea is used as a “peripheral skirt” to provide tissue into which the prosthetic implant can incorporate itself.

The surgery takes about two hours, and the bandages are removed the next day. Patients are treated with steroids and antibiotics and usually recover fully in about a year. Glasses or contact lenses are typically prescribed to enhance sight restoration.

It’s always an emotional moment when the bandages come off and a patient can see again, said Lee, who performs about two artificial cornea transplants per month. “These are patients who at best could only see light. After the surgery they can dress themselves, cook and watch TV again. There aren’t many scenarios in medicine where there’s such a dramatic change.”

Morales said when Lee removed the bandage from her mother’s eye, “she was laughing and crying at the same time” because she could see her children and grandchildren. “It’s better in every way,” Morales said. “Now she can see us.”

—Jennifer Kaylin

Nanoparticles loaded with siRNAs are new vehicle for silencing genes in pathogens

During the past 10 years researchers have puzzled over how best to deliver small interfering RNA (siRNA) molecules, whose therapeutic value lies in their ability to shut down genes in higher organisms and in pathogens that may cause sexually transmitted infections (STIs).

Lipid-based formulations, the most widely used siRNA delivery vehicles, suffer from certain limitations. In particular, they are unable to provide sustained release of siRNAs that may be required for many applications, and they may be toxic to target tissues.

Now, as reported in Nature Materials in May, Yale scientists have found a safe and effective way of administering siRNA molecules. “We wanted to develop a new strategy of delivering siRNAs with an FDA-approved material,” said lead author Kim Woodrow, Ph.D., a postdoctoral fellow working with W. Mark Saltzman, Ph.D., the Goizueta Foundation Professor of Biomedical Engineering and Chemical Engineering.

For this proof-of-principle work, the researchers designed siRNAs to target a gene expressed widely in the lining of the female mouse reproductive tract. Saltzman and Woodrow used densely loaded nanoparticles made of PLGA, an FDA-approved biodegradable polymer, to create a stable time-release vehicle for delivering siRNAs to mucosal tissue.

To convert an FDA-approved material into an siRNA delivery system, the particles needed to be small enough to penetrate tissue barriers and be taken up by cells. These nano sized particles also required stable incorporation of large quantities of siRNA. Saltzman and Woodrow demonstrated that their siRNA nanoparticles were distributed and retained throughout the female reproductive tissue. They also showed that delivery of siRNA by PLGA nanoparticles resulted in sustained gene silencing in the tissue for up to 14 days.

“Before human clinical testing can begin, our next step in research will be to test this approach directly in disease models—for example in the HIV-model mice that have an immune system genetically identical to that of humans,” said senior author Saltzman.

This approach may lead to antimicrobial treatments that patients can apply themselves. “It is safe and effective, and much easier than getting an injection of vaccine,” Woodrow said.

—Janet Emanuel

et cetera

$4 million for stem cell research

The state of Connecticut in April awarded close to $4 million to Yale scientists to study ways in which human embryonic stem cells can be used to treat such ailments as spinal cord injuries, cancer, and mental retardation. The grants were made by the Connecticut Stem Cell Research Advisory Committee, formed in 2005 when the state allocated $100 million over 10 years to promote such research. Connecticut was the third state to pass legislation allocating funds for the study of embryonic stem cells.

Five Yale researchers received grants worth a total of $2.5 million, and seven others received seed grants worth a total of $1.4 million. This latest round of funding will support such research projects as remyelination of nonhuman-primate spinal cords and the use of transposons—sequences of DNA that can change position within the genome of a single cell—for genetic manipulation of human embryonic stem cells.

—John Curtis

Markers for prostate cancer

Scientists at Yale and the VA Connecticut Healthcare System in West Haven have reported a link between molecular markers and higher death rates from prostate cancer. The paper appears in the May 5 issue of the Annals of Internal Medicine.

Amidst an ongoing debate in the medical community over whether screening and early diagnosis of prostate cancer save lives, or whether the aggressiveness of the tumor is more relevant in determining survival, the scientists studied tissue from biopsies of more than 1,000 veterans diagnosed with prostate cancer between 1991 and 1995. They found that abnormal expression of the Bcl-2 gene or of the p53 tumor suppressor gene increased the likelihood of patients’ death from prostate cancer.

“Our results expand the current ability of clinicians to evaluate the aggressiveness of prostate cancer,” said lead author John Concato, M.D., M.P.H., professor of medicine. “Future research can help to define specific biologic mechanisms and develop new therapies.”

—J.C.


			Originally published in Yale Medicine, Autumn 2009. Copyright © 2009 Yale School of Medicine. All rights reserved.