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Gene therapy offers hope for hereditary blindness
FORT LAUDERDALE, Fla. — Gene transfer therapy has successfully halted retinal degeneration and improved visual acuity in young adults with Leber’s congenital amaurosis, two separate groups of clinical investigators announced during the Association for Research in Vision and Ophthalmology meeting here.
Both researchers’ findings were published online recently in the New England Journal of Medicine. Both studies represent the first successful application of gene therapy in human patients for the debilitating retinal condition.
One group, led by researchers from the University of Pennsylvania and the Second University of Naples, Italy, outlined its results at a press conference here. The other group, led by researchers from the Moorfields Eye Hospital in London, presented its findings at a symposium during the meeting.
“We consider this a stepping stone to a new age, where the same strategies and the same agents can be used to treat conditions that are far more prevalent,” Jean Bennett, MD, PhD, of the University of Pennsylvania, said. “An example would be Stargardt’s disease.”
Dr. Bennett was joined at the press conference by Katherine A. High, MD, and by phone by her husband, Albert M. Maguire, MD, and Alberto Auricchio, MD, from Italy.
In both studies, patients were injected with a normal version of the gene RPE65, a retinal pigment epithelium-specific protein, which is mutated in patients with one form of Leber’s congenital amaurosis.
In the University of Pennsylvania-led trial, three patients were enrolled: one 19-year-old woman and a set of 26-year-old twins, male and female, under the supervision of Francesca Simonelli, MD, from the Second University of Naples. They each received the therapy between October and January at the Children’s Hospital of Philadelphia and were followed for 6 months.
These investigators reported that patients were able to read 3.5 lines after a single injection, whereas at baseline they were limited to hand motion perception. Researchers also reported that the injected eye became about three times more sensitive to light. One patient showed improvement in navigating an obstacle course, and all three had reduced signs of nystagmus.
“After injecting the study agent into one eye, we evaluated a number of systemic and ocular findings to look for toxicity,” Dr. Maguire said. He noted that the researchers used stringent objective and subjective criteria to eliminate any uncertainty over the validity of the results.
Regarding adverse effects, one patient developed a macular hole that did not appear to affect vision.
“It was thought it was related to surgery and not the vector, and a modification was made to prevent this in future procedures,” Dr. Bennett said.
The researchers plan to follow the patients for 15 years over a prescribed series of time intervals, which will taper off to an annual follow-up after a year and a half. They have also injected one other subject and have lined up two more patients who are willing to undergo this treatment.
 James W.B. Bainbridge |
In the second group, from Moorfields Eye Hospital, James W.B. Bainbridge, PhD, FRCOphth, said visual results were promising, and there were no complications from surgery or any toxic effects. This study also looked at three adults who were between 17 and 23 years old.
In one patient, improvement of three lines was seen, but it was not clinically significant because improvement was also detected in the untreated eye, Dr. Bainbridge said. Yet one patient exhibited five times more retinal sensitivity 6 months after surgery, with no improvement in the untreated eye. Another patient demonstrated dramatic improvement in navigating a controlled spatial environment and reported feeling more confident while maneuvering it.
Dr. Bainbridge said the group is encouraged by its findings so far, and a trial is already beginning in children.
In light of the publicity that surrounded both of these studies here, some audience members called for caution when interpreting these results until it is conclusively established that the treatment has a direct anatomic effect on patients.
These items appeared originally as daily coverage from the meeting on OSNSuperSite.com. Look for more in-depth coverage of these and other topics in upcoming issues of Ocular Surgery News.
Outgoing ARVO president calls for increased international involvement
 Lois E.H. Smith, MD, PhD, delivered a lecture on pediatric retinopathy upon receiving the Friedenwald Award, given in recognition of her ongoing work at the Children’s Hospital at Harvard Medical School. Delivering her award lecture, titled ‘Retinopathy through the Eyes of a Child,’ Dr. Smith focused largely on retinopathy and its relationship with prenatal births. Images: Kelly A, OSN | ||
An emphasis on international expansion and a call for increased member involvement on a global basis were the main points delivered by Martine J. Jager, MD, PhD, outgoing ARVO president, in a speech.
“I am very pleased that 142 young, non-U.S. researchers were awarded travel grants to be able to attend this year’s meeting,” Dr. Jager, who is from The Netherlands and is ARVO’s first non-U.S. president, said during the Keynote Session, which opened the annual meeting. The session was sponsored by Alcon.
“As president this year, I was invited to speak at both the Brazil and the Israel ARVO chapter affiliate meetings. And later this year, along with other ARVO members in Europe, I will represent ARVO at a newly formed Hungarian and also a Dutch chapter meeting,” she said. “As international membership continues to grow, I hope to see that more countries will start chapters with ARVO.”
Dr. Jager recalled that ARVO was formed in 1928 by 73 U.S. ophthalmologists.
“Eighty years later, ARVO has evolved into an international organization with over 12,000 members from 70 different countries,” she said.
Dr. Jager also called for members to volunteer their time to work on organization committees and governance. She encouraged them to learn more about the organization’s first draft copy of its international advocacy handbook, which was presented during the meeting.
Todd P. Margolis, MD, PhD, assumed the presidency at the organization’s annual business meeting.
Receiving distinguished service awards at this year’s keynote session were past president Frederick L. Ferris III, MD, past vice presidents Robert B. Barlow, PhD, and Daniel T. Organisciak, PhD, and Robert N. Frank, MD, editor in chief of Investigative Ophthalmology & Visual Science.
The special recognition award was given to Andrew B. Watson, PhD, current editor-in-chief of the Journal of Vision.
Highlighting the evening’s events was the Keynote Lecture delivered by author and innovator Ray Kurzweil, speaking on “The Democratization of Innovation in an Era of Accelerating Technologies.”
Mr. Kurzweil is responsible for the first print-to-speech reading machine, developed in the late 1970s. He has received prestigious awards such as the MIT-Lemelson prize and a 1999 National Medal of Technology, presented by President Clinton.
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Retina
Adding topical NSAID to anti-VEGF therapeutic regimen reduced number of injections
Fewer intravitreal injections of ranibizumab were needed to treat patients with choroidal neovascularization secondary to age-related macular degeneration when those patients also were treated with topical bromfenac, according to a poster presentation.
“Inflammation has a salient role in membrane formation and maintenance, so that’s why we targeted this with a nonsteroidal anti-inflammatory,” Calvin A. Grant, MD, told OSN.
Dr. Grant conducted a controlled study that evaluated 60 patients who received Lucentis (ranibizumab, Genentech) injections for AMD. Thirty of the patients were treated with ranibizumab alone. The other 30 patients received Xibrom (bromfenac ophthalmic solution, Ista Pharmaceuticals) 0.09% topically twice a day, in addition to the ranibizumab injection. Researchers compared the results from both groups.
Dr. Grant said the patients were evaluated each month with optical coherence tomography and fluorescein angiography. Those patients who had leaking vessels were re-injected with ranibizumab.
During the 6-month interval, the ranibizumab-only patients needed an average of 4.5 injections. Patients who had bromfenac added to their treatment regimen needed an average of 1.6 injections over the same interval.
The patients in the combination group also showed a statistically significant improvement in visual acuity, Dr. Grant said.
Their mean visual acuity increased 1.2 ± 1.64 lines compared with 0.06 ± 0.66 lines in patients in the ranibizumab-only group (P = .001), according to the poster.
Combination PDT, ranibizumab more effective against CNV than monotherapy
 Michael A. Dyer, PhD, spoke about the role of the Rb family in retinal development and retinoblastoma after receiving the Cogan Award, given to a researcher under the age of 40 who shows promise for future research-related contributions. Dr. Dyer is currently focusing on the regulation of growth during neural development at St. Jude Children’s Research Hospital in Memphis, Tenn. | ||
Combination treatment with photodynamic therapy and intravitreal ranibizumab requires fewer re-treatment injections against subfoveal choroidal neovascularization than ranibizumab alone, according to a speaker here.
“You need significantly less re-injections if you combine PDT with Lucentis, but the timing of re-injection is still unpredictable,” Beatrice Braun, MD, told Ocular Surgery News in an interview after her presentation. “We still have to investigate the patients monthly to maintain the initial gain of visual acuity after the initial three doses.”
Dr. Braun and colleagues at University Eye Hospital in Basel, Switzerland, are conducting the ongoing randomized, controlled trial comparing the ranibizumab monotherapy with combination therapy using standard fluence PDT and ranibizumab. Of the 37 patients who completed the trial, 19 were given monotherapy and 18 had the combination therapy.
Patients were randomly assigned to receive initial PDT or sham PDT, followed by three initial monthly 0.3-mg intravitreal ranibizumab injections. Patients who suffered a loss of more than five letters of best corrected visual acuity or an increase in central retinal thickness more than 100 µm, as shown on optical coherence tomography, received additional injections as needed.
During the first 6 months of the study, 29.7% of all patients needed re-injections — 42.1% in the monotherapy group and 16.7% in the combination group. Neither group showed a significant difference in re-treatment indications.
Pan-VEGF blocker sustained benefits in AMD patients through extended follow-up
A novel VEGF-blocking agent known as VEGF Trap-Eye has been shown to sustain improvement in visual acuity and decrease in retinal thickness after 32 weeks, according to a study.
Diana V. Do, MD, one of the study investigators from Wilmer Ophthalmological Institute, presented interim data from the prospective, multicenter phase 2 study.
VEGF Trap-Eye (Regeneron Pharmaceuticals/Bayer HealthCare AG) was studied in 159 patients with age-related macular degeneration who were randomly assigned to five dosing groups and treated with the agent in one eye, according to Dr. Do. Two groups initially received monthly doses of 0.5 mg or 2 mg for 12 weeks, and three groups received 0.5 mg, 2 mg or 4 mg of VEGF Trap-Eye at baseline and at week 12, she said.
After this initial fixed-dosing schedule phase, patients received the same doses of therapy, only on an as-needed basis governed by the physicians’ assessment of pre-selected criteria, she said.
“At week 16, 58% to 84% of subjects gained visual acuity, and this effect was sustained and increased through 32 weeks of follow-up,” Dr. Do said.
All groups in the study maintained their improvement in visual acuity — a mean of 6.6 letters — through the 32-week follow-up visit. They also maintained a decrease in retinal thickness, demonstrating a mean 137-µm decrease compared with baseline.
Investigators said the groups that were initially dosed quarterly, although they maintained their functional and anatomical gains, did not demonstrate as much improvement as those who initially were dosed monthly.
The researchers said there were no serious drug-related adverse events. There was one reported case of culture-negative endophthalmitis/uveitis in the treated eye, but this was not considered to be drug-related. Other non-serious effects were those typically associated with intravitreal injections.
Researchers also noted a “statistically significant reduction in [choroidal neovascularization] leakage and CNV lesion size, so it suggests that VEGF Trap-Eye causes a regression of CNV leakage,” Dr. Do said.
Although the researchers are not certain what causes the durability of effect, Dr. Do said they hypothesize that the agent’s unique molecular structure lends it “greater bioactivity and longer sustainability of action.” The durability is one factor that will be studied in two simultaneous phase 3 studies, VIEW 1 and VIEW 2, that are currently under way to evaluate two dosing schedules at 4-week and 8-week intervals compared with ranibizumab administered every 4 weeks.
BRVO patients improve after injections of anti-VEGF agent
Pegaptanib appears effective in improving vision and reducing central thickness in patients with branch retinal vein occlusion, according to study results presented in a poster.
“Larger randomized clinical trials are needed to confirm this hypothesis,” the study authors said.
John J. Wroblewski, MD, and colleagues prospectively evaluated the safety and efficacy of 0.3-mg and 1-mg injections of Macugen (pegaptanib sodium, OSI Eyetech/Pfizer) in treating 20 eyes of 20 patients with macular edema secondary to BRVO. The patients were randomized to receive one of the two doses at six weekly intervals for 12 weeks. After the 12-week point, they were treated on an as-needed basis, according to the poster.
The investigators found that patients had gained an average of 11 letters of visual acuity 1 week after the first injection. Center point thickness decreased by 210 µm, and mean macular volume decreased by 2 mm³.
At 30 weeks, the average gain in vision was 13 letters, the average decrease in center point thickness was 225 µm, and the average decrease in macular volume was 2.3 mm³.
PHP detects conversion from dry AMD to wet
The use of preferential hyperacuity perimetry can detect the conversion of the dry version of age-related macular degeneration to the more destructive exudative form of the disease, according to results from a study.
“In some cases, the patient hasn’t even realized any [visual] changes yet,” Yuhua Lai, research coordinator, said during a poster session.
The preferential hyperacuity perimetry exam helps practitioners identify elevations in a patient’s retinal pigment epithelium and the bowing of the photoreceptor layer by having patients identify bends they see in line targets on a computer screen.
The analysis was conducted within the multicenter Cost of Age-Related Macular Degeneration (CARMA) trial in which 135 patients with late AMD in one eye and 65 patients with intermediate AMD in both eyes were enrolled between June 2004 and March 2007.
Before October 2007, nine of the patients progressed to wet AMD and eight of those patients showed abnormalities during the Foresee PHP (Notal Vision/MSS) test, Ms. Lai said. Optical coherence tomography helped confirm the diagnosis.
A version that patients can use at home is currently in clinical trials, she said.
Awareness of stress triggers in patients’ lives can help mitigate uveitis flare-ups
Stress may be a modifiable risk factor for acute anterior uveitis flare-ups, according to a poster presentation.
“It was our clinical impression that many patients with HLA-B27 positive uveitis related the recurrences to stress and stressful life events,” Saskia M. Maca, MD, of the Medical University of Vienna, told OSN.
Questionnaires were sent to nearly 400 patients of the uveitis unit at the university, and 171 responded to a standardized psychological questionnaire, as well as a socio-demographic data sheet, and questions about stress and trigger situations, according to the abstract.
About 58% of the respondents said their flare-ups were triggered by stressful life events, including a death in the family, separation or divorce, illness and difficulties at work.
Clinicians should be aware of the relationship between stress and flare-ups and advise patients appropriately. Doing so may help their quality of life, Dr. Maca said.
“We tell our patients about this theory, especially the ones who are new with this disease,” she said. “A lot of patients later on tell us, now that they know stress might be a trigger, they look out for the situations and try to better deal with them.”
Dr. Maca said her next goal is to look at how hormones influence flare-ups.
“It might be interesting to look at serotonin levels in the future,” she said.
National genotyping network growing, but seeks more patients for research
A network that began as a way to manage molecular diagnosis and clinical data for use in research is expanding and seeking more help from clinicians, according to a poster presenter.
“Last ARVO we only had about 80 samples in the network,” Santa J. Tumminia, PhD, said about The National Ophthalmic Disease Genotyping Network (eyeGENE). “Now, at this ARVO, we have a little over 350 samples in the network. It’s growing. People are becoming more and more interested.”
Patients have been recruited from centers, private practices or the National Eye Institute. After they are enrolled, patients consent to be tested and must be offered genetic counseling. The patient’s blood is drawn and sent to a lab for molecular diagnostic testing. Next, eyeGENE collects demographic information, diagnosis and phenotypic data, according to the abstract.
Dr. Tumminia said the group’s next challenge is recruiting clinicians who have patients to enter into the database.
“Our main purpose is to facilitate research in genetic diseases, but in order to do that we need patients,” she said. “The hardest part is actually getting the health care provider to go online and enter the information for their patients.”
The network, which is funded by the NEI at the U.S. National Institutes of Health, is composed of 10 CLIA-certified laboratories that provide testing for 50 genes responsible for 20 eye diseases, including retinal diseases, strabismus, glaucoma and corneal dystrophies.
Ultimately, Dr. Tumminia said her aim is for the eyeGENE database to be used for research.
“The next goal is going to be opening up the repository and the database to researchers,” she said. “In order to do that, there needs to be substance behind it. It’s only going to be as good and robust as the system actually is. The more patients, the better.”
For more information, visit the eyeGENE Web site at www.nei.nih.gov/resources/eyegene.asp.
Glaucoma
Anecortave acetate shown to lower IOP in different forms of glaucoma
A study in Brazil has concluded that an anterior juxtascleral depot of anecortave acetate can significantly reduce IOP for at least 3 months in several types of glaucoma.
“These are all severe cases, all patients without controlled IOP, despite using medication,” Tiago S. Prata, MD, told OSN, in an interview at his poster. “Most of them required surgery or additional medication, and instead of doing the surgery, we enrolled them in the study.”
The prospective, nonrandomized open-labeled clinical trial treated 25 eyes of uncontrolled glaucoma patients with a single anterior juxtascleral depot of 30 mg of anecortave acetate (Alcon) under topical anesthesia. The eyes were assessed after 1 week, 1 month and 3 months. A mild subconjunctival hemorrhage was observed in four cases. One eye developed a small and transient corneal dellen at the first week, according to the poster abstract.
“We didn’t have any major complications with the injections: no pain because the patients are under anesthesia, no decrease in visual acuity and only mild foreign body sensation,” Dr. Prata said.
The mean IOP of the study patients was 30.9 ± 9.2 mm Hg at baseline, 20.9 ± 7.5 mm Hg at the first month, 21.5 ± 7.6 mm Hg at the second month and 19.1 ± 5.2 mm Hg at the third month. Those eyes with angle-closure glaucoma showed a mean IOP of 17.4 mm Hg, and open-angle glaucoma cases showed a mean IOP of 20.7 mm Hg.
“It’s a huge IOP decrease with only one injection and no need for additional medication,” Dr. Prata said.
New test for peak IOP is faster, easier, researcher says
A 5-minute provocative test that inverts a patient’s body 30° is as good as a standard water drinking test in detecting peak IOP in glaucoma patients, according to a poster.
“The test is easier, faster and more comfortable for patients,” Fabio N. Kanadani, MD, said. “It is based on yoga practices.”
Researchers tested 18 normal eyes, 30 glaucoma suspect eyes and 31 eyes with early glaucoma. During the test, they had the patient lie in a 30· supine position with his or her head pointed downward. IOP measurements were taken with a Perkins applanation tonometer after 5 minutes.
Researchers also had the patients take the normal water drinking test. During that test, patients fasted before drinking 1 liter of water in 5 minutes. Four measurements were performed with standard achromatic perimetry at basal, 15 minutes, 30 minutes and 45 minutes.
“Our results show that there was a statistical difference in both test groups between the basal IOP and the peak IOP,” Dr. Kanadani said. “The inverted test is just as good as the water test in detecting peak IOP, and it doesn’t take an overnight stay in the hospital to perform.”
New online resource seeks to fill knowledge gap in optic nerve imaging
A new online resource geared to help clinicians better understand technologies available to examine the optic nerve was launched last week.
Pfizer Ophthalmics announced the debut of the Optic Nerve Resource Center, housed on the Web site www.alleyesonglaucoma.com, at a press conference.
The resource is geared for physicians — both comprehensive ophthalmologists and glaucoma specialists — to learn about the latest technologies available to examine the optic nerve to detect anatomic damage before functional vision loss, according to OSN Glaucoma Section Member Robert N. Weinreb, MD, who spoke on the site’s advantages during the press conference.
“I don’t believe physicians have a ton of resources. Many glaucoma experts, even, have not learned well in their training,” Dr. Weinreb said. “What this hopefully will do is to be a source of information that integrates and accumulates information on optic nerve examinations. Although someone can buy a book or attend a course, this is something that is unique.”
Currently, the site focuses on confocal scanning laser ophthalmoscopy, scanning laser polarimetry and optical coherence tomography. Officials from Pfizer said the site will be updated as the category of imaging technology evolves and as more published data become available.
Cornea/External disease
 George O. Waring III, MD, FACS, FRCOphth, was presented with the Mildred Weisenfeld Award for distinguished scholarly contribution to ophthalmology. Dr. Waring spoke on the need to improve pre- and postoperative standards when performing refractive surgery. While trumpeting the procedure and its impact worldwide, he also suggested improvements such as preoperative psychological testing, possible simulation of outcome and improved postoperative quality-of-life questionnaires. | ||
Endoscopic corneal video features groundbreaking imaging
A team of researchers is seeking to advance ophthalmic imaging through the use of three- and four-dimensional endoscopic confocal renderings of the cornea after corneal inlay implantation.
George O. Waring IV, MD, presented his results in a poster presentation.
Dr. Waring and colleagues utilized confocal microscopy imaging with the Confoscan 4 (Nidek Technologies) on both eyes of one patient who had been implanted in one eye with the AcuFocus corneal inlay. They then employed Analyze software 7.0 (Biomedical Imaging Resource) to create an endoscopic confocal corneal “fly through” video of both the implanted and control eyes.
The video of the implanted eye was analyzed by two independent observers for evidence of keratocyte hypercellularity, inflammatory cells or any alterations to the epithelium. When compared with the video of the control eye, it revealed a well-tolerated implant with no signs of negative effects.
An advantage of the technique is the ability to observe the spatial relationship of the implant to the surrounding cellular layers, according to the researchers.
“Qualitatively, it allows us to, at a single glance, correlate all the different cellular layers ... so that you can see an AcuFocus inlay or any inlay that remains well-tolerated after an implantation and how it affects the other cellular layers,” Dr. Waring said.
The technique will not only help expand research possibilities but could also impact other imaging devices that could incorporate the technology, he said.
“My vision for this is, instead of a patient sitting down in a clinic and having a slit lamp photo of their eye and then having an animated video play next to it, you actually can take them on a ‘fly through’ of their own eyeball,” Dr. Waring said.
Topical cyclosporine halts progression of dry eye better than tears, study shows
The use of topical cyclosporine is more effective than artificial tears at increasing goblet cell density and halting the progression of dry eye disease, according to the results of a study presented here.
The single-center clinical trial enrolled 74 patients between February 2006 and January 2007, and 58 of the patients completed the 12-month study, according to Sanjay N. Rao, MD, who presented the results.
Patients were randomized to twice-daily treatment with either cyclosporine 0.05% (Restasis, Allergan) or artificial tears (Refresh Endura, Allergan), according to the study abstract. Outcomes were measured with Schirmer’s test, the Ocular Symptom Disease Index, tear break-up time, staining, and goblet cell density at baseline and months 4, 8 and 12, the abstract said.
Patients who received cyclosporine treatment were less likely to have progression of dry eye: 5.5% of 36 cyclosporine patients compared with 31.8% of 22 artificial tears patients (P = .007). The cyclosporine patients also were more likely to have the disease halted or improved: 94% with cyclosporine vs. 68.2% with tears (P = .007).
Patients using artificial tears were more likely to discontinue their treatment regimen, the study showed.
Light scatter found to decrease after DSEK but is still higher than normal
Backscattered light from the cornea decreases after Descemet’s stripping with endothelial keratoplasty but still remains higher than normal in the posterior two-thirds of the cornea, according to an ophthalmologist.
Keith H. Baratz, MD, and colleagues from the Mayo Clinic College of Medicine, Rochester, Minn., conducted a prospective, non-randomized study in 18 eyes of 16 patients, all with corneal edema from Fuchs’ dystrophy.
Patients were evaluated preoperatively and at 1, 3 and 6 months postoperatively and were compared with a control group of 41 eyes in 41 patients.
Best corrected visual acuity was also measured. Researchers used ETDRS testing protocol, with mean BCVA reported at 0.46 ± 0.24 logMAR before surgery, 0.31 ± 0.22 logMAR at 3 months and 0.27 ± 0.14 logMAR at 6 months, according to Dr. Baratz.
Contrast sensitivity was tested using the Functional Acuity Contrast Test (Vision Sciences Research Corp.).
Before surgery, backscattered light was 69%, 55% and 115% higher than normal in the anterior, middle and posterior regions of the cornea, respectively. At 6 months after surgery, backscattered light decreased but still remained 22% higher than normal in the middle region and 30% higher than normal in the posterior region.
Contrast sensitivity was significantly lower than normal after Descemet’s stripping with endothelial keratoplasty.
A note from the editors:
To facilitate bringing news to readers rapidly, for OSN SuperSite articles and meeting wrap-up articles, OSN departs from its editorial policy and typically does not send these items out for source corrections.