The achievement is based on a technology in which the cells are introduced at a particular stage in their development. It was carried out at the Institute of Ophthalmology using an approach developed at the University of Michigan Kellogg Eye Center to tag rod precursor cells and prepare them for transplantation.
The transplanted photoreceptor precursor cells survived and became integrated into the mouse retina, and the technique succeeded because the cells were isolated when they had reached a certain level of maturity. Rather than injecting undifferentiated and uncommitted stem cells into the retina in hopes they would develop into photoreceptors, researchers introduced cells at a somewhat later stage. These cells are referred to as "precursors," immature cells that are "programmed" to be, but have not yet become, functionally mature photoreceptors.
The findings, reported in the November 9 advance online issue of Nature, come from the collaborative research of Anand Swaroop, PhD, the Harold F. Falls Collegiate Professor of Ophthalmology and Visual Sciences at the University of Michigan Medical School, and Robin R. Ali, PhD, professor in the Division of Molecular Therapy at the Institute of Ophthalmology.
The technology represents a breakthrough in transplantation-based therapies for neuro-degenerative diseases. It suggests that scientists may need to introduce changes in stem cells in order for them to become highly specialized neurons.
Dr. Swaroop anticipates that several years of research using animal models and cell culture systems will still be needed before transplantation can be considered ready for testing in humans. The next wave of research will focus on characterizing the mechanisms that generate photoreceptor precursors from stem cells. Dr. Swaroop believes the research has potential for developing therapies for people with retinal and macular degenerative diseases that are untreatable today.
Drs. Ali, Swaroop and their colleagues report that the transplanted cells in diseased mouse retinas have met several essential requirements. The cells: survive; correctly develop into rod photoreceptors; integrate and connect in sufficient numbers to neurons that ultimately carry visual signals to the brain; and they have proven to be functional.
The photoreceptor precursors were transplanted into three different types of mice with retinal degeneration caused by distinct genetic defects involving malfunctioning or degenerating rods. The transplanted cells survived and were functional for the duration of the study. Scientists observed improvements including pupil response to light and response to light stimuli from ganglion cells, which form the circuitry to the brain.
Dr. Swaroop explains that photoreceptors constitute "the first line of information capture in vision." They are part of a complex sensory system that delivers visual signals to the brain. Photoreceptors consist of rods and cones, highly specialized cells that capture light and convert it into chemical signals that travel through the inner retina and optic nerve and on to the brain where signals are converted to the images we see. In the majority of macular and retinal degenerative diseases, such as age-related macular degeneration and retinitis pigmentosa, it is the loss of photoreceptors that leads to blindness.
The new paper shows that successful transplantation requires that cells reach a certain level of maturity before being transplanted into the eye. When the cells were transplanted at a very early stage, before they were assigned their specialized function, they survived but failed to integrate into the mature retina. Only one group of cells remained viable: cells that were not yet mature, but had developed to the point at which they were committed to becoming rods.
After almost two decades of directing fundamental research on retinal development and degenerative diseases, Dr. Swaroop believes that scientists are at last entering a period of rapid discovery. "This provides a clear example of how basic fundamental research can contribute to treatment of blinding diseases," he says. "We now have proof of principle that our approach to repairing damaged retina by transplantation of appropriate cells can be successful."
Dr. Swaroop sees several next steps in his quest to find treatments for retinal and macular degeneration. His research team will continue to study the properties of photoreceptor cells and mouse models to learn more about the process of transplantation and functional integration. He hopes that he will soon be able to investigate how the concept of transplanting photoreceptor precursors can be adapted to the human retina. "Perhaps within the next five years we will begin to see the first steps toward retinal cell transplants for people with blinding eye disease," says Dr. Swaroop.
Walking Away From AMD
An active lifestyle can reduce the risk of developing age-related macular degeneration, according to researchers with the University of Wisconsin Department of Ophthalmology and Visual Sciences.
"Individuals that exercised regularly (defined as three or more times per week) were 70 percent less likely to develop wet AMD than non-active individuals," said Michael D. Knudtson, MS, lead researcher of the study. "Additionally, those who walked regularly were linked to a 30 percent reduced risk of developing wet AMD."
Mr. Knudtson and his team measured the 15-year cumulative incidence of AMD through four examination phases at five-year intervals of a population-based study conducted in Beaver Dam, Wis., initiated in 1988 (n=3,874 men and women between ages 43 and 86 years). Early AMD (pigment abnormalities or soft indistinct drusen), exudative AMD and geographic atrophy were determined by grading stereoscopic color fundus photographs. Physical activity were measured through a questionnaire administered at the baseline examination.
After controlling for age, sex, history of arthritis, systolic blood pressure, body mass index, smoking and education, people with an active lifestyle (defined as regular activity three times a week) at baseline were less likely to develop exudative AMD compared with people without an active lifestyle. After multivariate adjustment, increased categories of number of blocks walked per day decreased the risk of exudative AMD. Physical activity was not related to the incidence of early AMD or pure geographic atrophy.
"This study provides evidence that a modifiable behavior, regular physical activity such as walking, may have a protective effect against age-related macular degeneration, but I would like to stress that other lifestyle factors such as diet could not be ruled out as possible explanations for the relationship," added Mr. Knudtson.
Procedure May Alter Approach To Ocular Melanoma
A new procedure at UCLA's Jules Stein Eye Institute could reveal valuable information to ocular melanoma patients and their physicians, providing a clear basis for making treatment and lifestyle choices. Researchers there pioneered a technique to biopsy tissue from the living eye in order to predict which tumors possess high metastatic risk. The findings appear in the January 2007 Ophthalmology, and they urge a new treatment strategy for physicians and offer huge medical and psychological benefits to patients.
"For the first time, we have demonstrated that it's safe and feasible to perform a biopsy in the living eye to obtain clear results about whether a tumor has metastatic potential or not," said Tara Young, MD, assistant professor of ophthalmology at UCLA's Jules Stein Eye Institute and a Jonsson Comprehensive Cancer Center researcher. "Identifying patients at high risk for metastasis is an important first step toward reducing the death rate of this cancer, which kills nearly half of its patients."
Ocular melanoma attacks the pigment cells in the retina. Earlier studies discovered that patients who are missing one copy of chromosome 3 in their tumor tissue are more likely to have highly aggressive cancers. Half of these patients die within five years, due to metastasis to the liver and other organs.
Using this genetic marker as the starting point for their research, UCLA scientists studied a group of patients who had been newly diagnosed with ocular melanoma. Each patient was scheduled for a standard eye surgery to temporarily implant a small disc designed to shrink the tumor with radiation and hopefully save the eye.
For the first time, UCLA surgeons used an ultra-fine needle to collect cells from the cancer before surgery and send the sample to the lab for culture. After growing the tumor cells, a geneticist analyzed them to determine whether they were missing a copy of chromosome 3.
Of the nine patients in the UCLA study who underwent biopsy, four had tumors identified as high-risk for aggressive metastasis, and five were identified as low-risk.
"When physicians know upfront which patient has a poor prognosis, they will monitor the person more closely to detect metastasis earlier and consider more aggressive treatments to increase their chance of survival," Dr. Young said. "Knowledge of metastatic risk will also help patients and their physicians decide whether to pursue clinical trials of experimental therapies that target metastasis.
"Patients understand that no good treatment exists after their cancer spreads—everyone wants to know what their metastasis risk is," she added. "If the risk is low, it's a giant relief and emotional burden off their shoulders. If the risk is high, it enables them to plan arrangements for their family and finances, and make the most of their remaining time alive."
The technique of fine-needle aspiration for collecting cancer cells from the living eye has been the standard of care at the Jules Stein Eye Institute since 2004, but adopted by only a handful of other ophthalmic centers in the nation.
"Until now, there's been little we could do but radiate the patient's eye and ask them to return for a follow-up exam in six months," said Dr. Young. "But it's short-sighted to think of ocular melanoma as related only to the eyeball. Cancer can kill you, regardless of where it originates in the body.
"We've known for 10 years that this genetic marker is linked to fast-growing melanoma," she added. "It's time for ophthalmologists to expand their surgical practice to include the biopsy procedure, and use it to obtain life-saving information for their patients. Only then will we be able to develop strategic approaches to treating the cancer's effect on the whole body."
