Scientists at the Scripps Research Institute have found that a drastic reduction of vascular endothelial growth factor activity may do more harm than good. Anti-VEGF therapy has become a mainstay in treating wet macular degeneration.
In the new study, the researchers deleted the gene for the blood-vessel growth factor VEGF, which has been implicated in stimulating abnormal blood vessel growth in a range of cancers and eye diseases, from cells in the retinas of adult mice. The results showed that without VEGF a large subset of light-sensing cells lost their main blood supply and shut down, causing severe vision loss.
“It’s becoming clear that VEGF has a critical function in maintaining the health of the retina, and we need to preserve that critical function when we treat VEGF-related conditions,” said TSRI Professor Martin Friedlander, MD, PhD, senior author of the new study, which appears in the November 2012 issue of the Journal of Clinical Investigation.
Several anti-VEGF drugs are already in use, and dozens more are in clinical trials against cancers and common eye disorders such as wet macular degeneration. However, to date there have not been extensive studies on the effects of such drugs on the normal role of VEGF, in part because it is hard to generate adult animals that lack the VEGF gene. When the gene is removed from the embryos of mice, in a standard knockout experiment, the mice fail to develop normally and die before birth.
In the study, Friedlander laboratory postdoctoral fellows Toshihide Kurihara, MD, PhD, and Peter D. Westenskow, PhD, found a way to delete the major VEGF gene from mice after the animals had grown to adulthood. To determine VEGF’s role in the retina, they confined the gene deletion to the animals’ retinal pigment epithelial cells, which nourish and repair the retina and are a major retinal source of VEGF. The result suggests that VEGF does have a crucial function in the adult retina.
“Only three days after we knocked down the gene, we observed the complete deterioration of the choriocapillaris, a layer of capillaries that is a major supplier of nutrients to the outer retina, the location of the rod and cone photoreceptors,” said Dr. Kurihara.
|
Nearby light-sensing cone cells, which are specialized for detecting color and fine detail in visual images, also rapidly lost their function, causing pronounced vision loss in the mice. Seven months after the knockdown of the VEGF gene, the retinal damage and vision loss were still evident. “The deterioration seems irreversible if VEGF is not present,” said Dr. Westenskow.
Rod cells, which support low-light and peripheral vision, were not affected by the VEGF-gene deletion. The researchers note that cone cells may be more vulnerable because they are unusually active metabolically and may be unable to withstand a significant decrease in blood supply. Cone cells also bear receptors for VEGF molecules and thus may require direct VEGF stimulation to remain healthy. In any case, even if only cone cells died and rod cells were spared, a patient would experience severe vision loss. “You’d be defeating your purpose if you dried up the abnormal blood vessel growth but at the same time killed off the cone cells,” said Dr. Friedlander.
Whether such side effects are happening with existing anti-VEGF treatments is unclear. While these assessments are possible, they have been considered prohibitively expensive and invasive.
Dr. Friedlander, however, now believes such studies are necessary and plans to conduct such assessments in AMD patients to determine whether the drugs are causing these adverse side effects. He notes that the evaluations may be particularly necessary for a new class of anti-VEGF drugs recently approved for use in the treatment of AMD—drugs that are much more potent and persistent than previous anti-VEGF agents.
Fortunately, anti-VEGF drugs are not the only possible strategy for treating pathological blood vessel growth, as the new study makes clear. VEGF-related tumors and eye conditions also involve the overproduction of low-oxygen signaling proteins known as HIFs. The team found that deleting the genes for these HIFs in retinal cells largely prevents blood vessel overgrowth in a standard mouse model—without affecting the normal-level production of retinal VEGF or causing eye damage.
“In light of the present findings, other strategies for treating these eye conditions could be a possibility,” Dr. Friedlander said. “Conceivably, an anti-HIF treatment could also be combined with an anti-VEGF treatment, allowing the dose of the latter to be lowered significantly.”
For more information on the paper, visit
jci.org/articles/view/65157.
Statins May Protect Some from Glaucoma
People who take statins to reduce their risk of cardiovascular disease are less likely to be diagnosed with the most common form of glaucoma, according to a nationwide study of more than 300,000 patients. A University of Michigan School of Medicine research team, directed by Joshua Stein, MD, MS, found that the risk for glaucoma was reduced by 8 percent in patients who took statins continuously for two years, compared with patients who did not take statins. The study, the largest to date on the topic, was published in the October issue of Ophthalmology.
Dr. Stein’s study was sparked by growing evidence that statin use may protect the optic nerve and retinal nerve fibers. His team used health-care claims data from 2001 to 2009 for a diverse population of Americans aged 60 and older who took statins to control hyperlipidemia. The researchers assessed patients’ risk for open-angle glaucoma. Unlike earlier studies, their analysis adjusted for patients who also had diabetes and/or hypertension to prevent distortion of the results.
Several of the study’s findings suggest that statin use may be most important before glaucoma is diagnosed, or in the early stages of the disease. Dr. Stein’s research may lead to new preventive treatments that could especially benefit groups at increased risk, including African Americans, Hispanics and those with a family history of glaucoma.
“Statins’ apparent ability to reduce glaucoma risk may be due to several factors, including improved blood flow to the optic nerve and retinal nerve cells and enhanced outflow of the aqueous fluid, which may reduce intraocular pressure,” said Dr. Stein. “While more research is needed, we hope our results may contribute to saving the sight of thousands who are predisposed to glaucoma.”
Dr. Stein cautioned that the study results apply only to patients with hyperlipidemia, and that further study is needed to determine whether statins also protect patients who don’t have this diagnosis or have other characteristics that differ from the study population.
First Transplant of Neural Stem Cells In Dry AMD Trial
StemCells Inc. announced that the first patient in its Phase I/II clinical trial in dry age-related macular degeneration has been enrolled and transplanted. The trial is designed to evaluate the safety and preliminary efficacy of the company’s proprietary HuCNS-SC product candidate (purified human neural stem cells) as a treatment for dry AMD, and the patient was transplanted with the cells at the Retina Foundation of the Southwest in Dallas. “This trial signifies an exciting extension of our ongoing clinical research with neural stem cells from disorders of the brain and spinal cord to now include the eye,” said Stephen Huhn, MD, FACS, FAAP, vice president and head of the CNS Program at StemCells. “Studies in the relevant animal model demonstrate that the Company’s neural stem cells preserve vision in animals that would otherwise go blind and support the therapeutic potential of the cells to halt retinal degeneration. Unlike others in the field, we are looking to intervene early in the course of the disease with the goal of preserving visual function before it is lost.”
David G. Birch, PhD, chief scientific and executive officer of the RFSW and principal investigator of the study, added, “We are excited to be working with StemCells on this groundbreaking clinical trial. There currently are no effective treatments for dry AMD, which is the most common form of the disease, and there is a clear need to explore novel therapeutic approaches.”
In February 2012, the company published preclinical data that demonstrated that HuCNS-SC cells protect host photoreceptors and preserve vision in the Royal College of Surgeons rat. Moreover, the number of cone photoreceptors, responsible for central vision, remained constant over an extended period, consistent with the sustained visual acuity and light sensitivity observed in the study. In humans, degeneration of the cone photoreceptors accounts for the unique pattern of vision loss in dry AMD. The data was published in the European Journal of Neuroscience.
The Phase I/II trial will evaluate the safety and preliminary efficacy of HuCNS-SC cells as a treatment for dry AMD. The trial will be an open-label, dose-escalation study, and is expected to enroll a total of 16 patients. The HuCNS-SC cells will be administered by a single injection into the space beneath the retina in the most affected eye. Patients’ vision will be evaluated using both conventional and advanced state-of-the-art methods of ophthalmological assessment. Evaluations will be performed at predetermined intervals over a one-year period to assess safety and signs of visual benefit. Patients will then be followed for an additional four years in a separate observational study. Patients interested in participating in the clinical trial should contact the site at (214) 363-3911. REVIEW
