As we enter a new year, it is an opportune time to look back at the past year to see what progress is being made in the field of AMD research. I have reviewed all the articles published on MyVisionTest over the past year and attempted to pick out the five most significant papers. There is no objective basis for this selection, simply my own opinion of which papers I think will make the biggest impact.

I also want to take this opportunity to wish everyone a happy, healthy and safe 2009.


#1 - SRC KINASE INHIBITORS SHOWS PROMISE IN PREVENTING MACULAR EDEMA


A research paper in the June 2008 edition of the Journal of Clinical Investigation involving mice and rabbits has found that VEGF-triggered fluid leakage can be prevented by a drug applied topically in eye drop form.

Investigators working with mice and rabbits found that a class of drugs called Src kinase antagonists may be applied topically in eye drop form and strongly inhibit VEGF-mediated vascular leakage. Such topically applied drugs may prove valuable in the clinical management of diseases in which excessive retinal edema due to VEGF-mediated abnormalities in vascular permeability leads to loss of vision, such as macular degeneration and diabetic retinopathy.

The availability of a topically applied inhibitor of vascular permeability would represent a major therapeutic advance in the treatment of retinal vascular disease. These findings offer hope of a potentially safe and painless topically applied therapeutic option for treating vision loss due to macular edema.


#2 - OMEGA-3 FATTY ACID INTAKE LOWERS RISK FOR AMD


Researchers performed a systematic review and meta-analysis on dietary omega-3 fatty acid and fish intake in the prevention of AMD and concluded that eating fish and other foods high in omega-3 fatty acids is associated with reduced risk for AMD, according to a paper published in the June 2008 edition of Archives of Ophthalmology.

The investigators examined 9 studies that enrolled a total of 88,974 people, including 3203 cases of AMD. High dietary intake of omega-3 fatty acids was associated with a 38% reduction in the risk for late AMD. Furthermore, eating fish at least twice weekly was associated with a 24% reduced risk of early AMD and a 33% lower risk of late disease.

This review of existing research reminds us of the important role that fish and omega-3 fatty acid consumption plays in helping to deter the onset and progression of AMD. The authors correctly express caution in making sweeping conclusions regarding the value of fish consumption in the prevention of AMD. Nonetheless, based upon currently available research, fish and omega-3 fatty acid consumption would appear to be second only to the AREDS formula in terms of the strength of existing research to support it's use to combat AMD. We look forward to AREDS2 to provide definitive information on the value of omega-3 supplementation.


#3 - STEROID PLUS PHOTODYNAMIC COMBO THERAPY FAILS TO SUSTAIN VISION GAINS OVER LONG-TERM


Researchers found that photodynamic therapy (PDT), when combined with intravitreal steroid injection will initially improve vision in patients with wet AMD, but these improvements are lost over a 24-month follow-up period, according to a paper published in the October 2008 edition of Archives of Ophthalmology.

Eighty-four patients were enrolled to receive PDT (n = 41) or PDT plus steroid therapy (n = 43). Patients were then followed for 24 months.

The researchers found that after an initial visual acuity benefit of combination therapy that lasts for at least 1 year there is a progressive visual decline during the second year of follow-up. After 2 years, there was no significant difference in the vision between the two treatment groups, and both groups had significantly worse vision than at the time of the initial treatment.

This study casts a shadow of doubt over the long-term vision benefits of photodynamic therapy. Although numerous studies have demonstrated the potential benefits of steroid-PDT combination therapy, this long-term study clearly demonstrates that these benefits may be transient. The authors remind us that at least 2 years of follow-up is necessary evaluate the lasting effects of any new treatment for wet AMD.


#4 - RETINA STEM CELL TRANSPLANTS SHOW PROMISE


Preliminary research shows encouraging results with transplantation of fetal stem cells in patients with retinitis pigmentosa (RP) and dry AMD, according to a report in the August 2008 issue of the American Journal of Ophthalmology.

Although they have different causes, both RP and AMD lead to destruction of retinal photoreceptor cells. In theory, if the damaged photoreceptors can be replaced with new cells it may be possible to restore visual function.

Investigators performed implantation of fetal retinal cells together with their attached retinal pigment epithelial cells in ten patients with vision of 20/200 or less: six patients with RP and four with the dry AMD.

Follow-up testing 5 years after implantation showed visual improvements in seven of the ten patients: three of the patients with RP and all four patients with AMD. Although vision remained in the "legally blind" range for all patients, the gains in vision were significant and measurable.

Currently, no effective treatment exists for the recovery of vision loss to degenerative retinal disease. But progress is being made. A clinical trial of gene therapy in Leber congenital amaurosis has recently reported good results. Neurotech has started phase II clinical trials for ciliary neurotrophic factor for RP. Multiple centers are actively pursuing development of a retinal prosthesis. The current study demonstrates promising results using fetal stem cell implants. There is reason to be optimistic that it will soon be possible to restore vision lost to these blinding diseases.


#5 - CLOSE MONITORING OF AMD HELPS PRESERVE VISION


A paper in the September 2008 edition of the journal Ophthalmology reports that close monitoring of patients with AMD can improve the ability to detect choroidal neovascularization (CNV) while it is still outside the fovea and vision is still good.

Results of 5 or more years of follow-up data from the Complications of Age-related Macular Degeneration Prevention Trial (CAPT) were analyzed.

The investigators conclude that when patients are monitored closely, many CNV lesions can be detected outside of the fovea and when they are relatively small. Early detection may lead to improved long-term visual acuity.

The authors write "close monitoring of high-risk eyes, such as fellow eyes in patients with unilateral CNV or eyes with multiple large drusen and pigmentary changes, can lead to detection of CNV when it is more likely to be outside the fovea, relatively small, and without a large loss in visual acuity. Regular retinal examinations, optical coherence tomography, preferential hyperacuity perimetry, and use of the Amsler grid may aid in early detection of CNV."

Nowadays, much of the vision lost to CNV is lost prior to the initiation of treatment. If CNV is found early, while vision is still good, the vision can usually be maintained.

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The Submacular Surgery Trials (SST) finds that patients with ocular histoplasmosis syndrome or idiopathic choroidal neovascularization do not perceive any improvement in the desirability of their overall health status after undergoing submacular surgery.

The SST investigated the outcome following surgical removal of subfoveal choroidal neovascular lesions that were either idiopathic or associated with ocular histoplasmosis. In 2004, they reported that there was little or no benefit to surgery.

In addition to clinical outcomes, the participants in SST answered a number of questionnaires regarding the quality of their vision and the ways that their vision impacted their overall quality of life. On average, patients that underwent surgery had a 4-point improvement in their National Eye Institute Visual Function Questionnaire (NEI-VFQ) compared to patients that did not have surgery at the 24-month visit. Therefore, there was a discrepancy between the clinical outcome (no benefit of surgery) and the quality of life survey (benefit of surgery).

To investigate the discrepancy between an improvement in vision-targeted quality of life and the lack of a significant difference in clinical outcome, the investigators began to administer the Vision Preference Value Scale (VPVS), a survey asking patients how they felt about the effects of CNV on their overall quality of life over time.

No significant difference was found in the median vision preference value of patients who had surgery and those that did not have surgery. This finding did not change when results were analyzed with respect to age, unilateral vs bilateral choroidal neovascularization, or good vs poor baseline visual acuity.

The investigators conclude that submacular surgery provided no benefit in the preference values that patients assigned to their health status. This indicates that submacular surgery for idiopathic and histoplasmosis-associated CNV does not enhance overall health-related quality of life.

WHAT IT MEANS TO YOU: This is further evidence that submacular surgery is not indicated for most patients with subfoveal choroidal neovascularization. The patients in this study were much younger than the average patient with AMD (both histoplasmosis and idiopathic CNV tends to affect younger persons), so one must be cautious in generalizing these results. Yet younger persons tend to have the greatest visual demands, and they fail to perceive any quality-of-life benefit from having this procedure.

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Decreasing abdominal obesity results in a lower risk for age-related macular degeneration (AMD), according to a new study.

Numerous studies have found an association between body mass index (BMI) and AMD. However, other studies have failed to find an association, or only found an association within certain subpopulations, such as women. Furthermore, potential mechanisms linking higher body weight with AMD are still unclear.

The waist-hip ratio (WHR) is a measure of central (abdominal) obesity. The WHR is calculated by dividing the waist circumference (maximum girth at the belly button) by the hip circumference (maximum girth at the buttocks). A WHR of 0.7 for women and 0.9 for men have been shown to correlate strongly with good general health.

Data for this study was drawn from the Atherosclerosis Risk in Communities Study, a population-based study of 15,792 persons drawn from 4 communities within the United States who were aged 45 to 64 years at baseline. The study participants were examined again 6 years after the initial examination.

The investigators compared the prevalence of AMD among persons with the greatest decrease in WHR (range: 3 - 44% decrease) to those persons with the greatest increase in WHR (range: 6- 102% increase). It was found that the group with the greatest decrease in WHR had a 29% lower risk of having AMD.

When the participants were grouped according to their weight at baseline, it was found that among participants who were obese at baseline, persons with the greatest decrease in WHR had a 59% lower risk of AMD.

The investigators conclude that middle-aged persons with a 3% or greater reduction in WHR over time were less likely to have AMD, particularly among those who were initially obese. They state that "our findings suggest a role of weight loss in preventing the development of AMD."

WHAT IT MEANS TO YOU: More evidence that a healthy lifestyle is one of your best protections against AMD. Together with not smoking and eating right, maintaining an ideal body weight is further insurance against developing this disease. Whether measured using BMI or WHR, losing weight, especially if you are obese, is one of the surest ways to stay healthy.

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Researchers have reported that stimulation of the mammalian target of rapamycin (mTOR) pathway can increase cone photoreceptor survival in mouse models of retinitis pigmentosa.

There is growing evidence that healthy rod photoreceptors are essential to cone photoreceptor well-being. The death of rod photoreceptors in a variety of diseases often leads to the later degeneration of cones. Studies of early AMD have found that rod loss preceded and was more severe than cone loss in most patients. It has been suggested that night vision difficulty, a sign of rod dysfunction, is a risk factor for progression of AMD.

To investigate why cone photoreceptors die in patients with RP, researchers probed the mTOR pathway in cone photoreceptors of mice with genetic mutations that cause an RP-like condition. The mTOR pathway functions as a sensor of cellular nutrient and energy levels.

In this study, the researchers found that activation of the mTOR pathway coincided with the time of cone photoreceptor death in mice with RP-like genetic mutations. This finding was interpreted as a sign that the cones may not be getting enough nutrients and that their energy levels were becoming low. The investigators then increased or decreased insulin levels and measured the survival of cones. They found that mice that were treated with insulin had prolonged cone survival.

The researchers conclude that cone death in retinitis pigmentosa could, at least in part, be a result of the starvation of cones.

"This is the first study linking cone death in retinitis pigmentosa to a metabolic problem that suggests starvation," says senior author Constance Cepko, of the Howard Hughes Medical Institute. "If we can find a way to supply nutrients to the cones, we might be able to preserve daylight vision in patients [with RP]."

WHAT IT MEANS TO YOU: By understanding what causes cells to die in diseases such as RP, we are in a better position to design effective therapies. By demonstrating the role of mTOR in the death of cone photoreceptors in RP, this study has opened the door to the development of new therapies for a variety of retinal diseases, including AMD.

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endophthalmitis among patients being treated for AMD with Avastin.

First noticed in British Columbia, authorities are trying to draw the potential problem to the attention of the global public health community in the hopes of seeing if it is being observed elsewhere.

The problem is believed to stem from a particular lot of the drug that was distributed widely around the world, though not to the United States. The lot number is B3002B028.

The drug's manufacturer, the Swiss pharmaceutical firm Roche, is co-operating with Health Canada and the British Columbia Centre for Disease Control, which was alerted to the problem by ophthalmologists.

The situation puts Roche in an awkward position. Avastin is a colon cancer drug; it is not approved for use as a treatment for AMD. Samantha Ouimet, a spokesperson for Roche Canada, said the company is reluctant to put out an advisory warning people not to use the drug as a treatment for AMD when the drug was never approved for this purpose.

A small portion, under two per cent, of people treated for AMD with Avastin will develop acute intraocular inflammation. But between Oct. 3 and Oct. 27, the rate was almost 10 times higher, according to the CDC.

The inflammation causes cloudy vision, but appears to clear up over time, Dr. David Patrick of the CDC said. Clinical features include toxic anterior segment syndrome (TASS) and variable vitritis.

Ouimet said there have been no reports of problems from other countries - and no reports of adverse reactions in cancer patients who received treatments from the same lot.

WHAT IT MEANS TO YOU: It is unclear why some patients develop a sterile endophthalmitis following intravitreal anit-VEGF injection. It may be an allergic-type reaction to the drug or one of the components in the solution that the drug is dissolved in. It could also be related to the procedure itself, the instruments used, or the medications administered before and after the procedure. Often patients that have developed sterile endophthalmitis following anti-VEGF therapy can safely resume treatment after the endophthalmitis resolves. Since it is unclear if, or how, the lot of Avastin in question differs from other lots of the drug, this episode just adds to the mystery surrounding sterile endophthalmitis. It is recommended that patients undergoing Avastin therapy confirm with their doctor that they are not using the drug lot in question, but otherwise not deviate from their normal treatment routine.

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The ongoing VEGF Inhibition Study in Ocular Neovascularization (VISION) clinical trial of Macugen (pegaptanib sodium) for age-related macular degeneration (AMD) has reported that no new safety concerns have emerged after 3 years of follow-up.

Macugen was in 2004 the first anti-VEGF drug to be approved for the treatment of AMD in the United States. Unlike Lucentis and Avastin, Macugen is a selective VEGF inhibitor, targeting only one variant (or isoform) of the VEGF molecule, leaving other isoforms unaffected. This selectivity may make Macugen less effective in combating choroidal neovascularization, but may also provide a safety benefit. VEGF is important for normal bodily functions; including wound healing, female reproductive cycling, bone growth, and maintenance of capillaries and neurons. The systemic use of anti-VEGF drugs in cancer treatment has been accompanied by increased incidences of systemic hypertension, bleeding, and blood clotting events.

In year 3, as in the previous years, adverse events were mainly ocular in nature, mild, transient and related to the injection procedure. The incidence of the most commonly reported ophthalmic adverse events (punctate keratitis, eye pain, vitreous floaters and cataract) decreased during the second and third years of the studies. There was no case of severe intraocular inflammation. The rate of endophthalmitis continued to decline over the course of the studies from 0.16% per injection in the first year to 0.10% per injection in the second year and to 0.06% per injection in the third year. The lower rate of endophthalmitis may be attributed to increasing familiarity with intravitreous injections by retina specialists over the course of this study.

No evidence of systemic safety problems attributed to VEGF inhibition arose in year 3.

The investigators conclude that data from the VISION trial demonstrate a favorable ocular and systemic safety profile for Macugen.

WHAT IT MEANS TO YOU: It appears that the most dangerous part of using anti-VEGF drugs in the treatment of AMD is the needle itself. No serious ocular or systemic side effects have been associated with either Lucentis or Macugen after 2-3 years of follow-up. We look forward to the development of topical drugs that can be applied in eye drop form to combat AMD, and thereby eliminate the most dangerous and inconvenient aspect of this treatment.

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Subthreshold diode micropulse (SDM) laser photocoagulation was found to be effective for chronic idiopathic central serous chorioretinopathy (CSCR) with juxtafoveal point source leakage according to a new research study.

CSCR is characterized by the accumulation of subretinal fluid (SRF) at the macula and is a common condition in young adults. Although CSCR is generally considered a self-limiting and benign condition, some patients may experience significant visual impairment caused by chronic or recurrent disease. Traditional management has been observation alone. At best, treatment with laser or drugs serve only to shorten the duration of symptoms and have no effect on the recurrence rate or the final visual acuity.

SDM laser treatment is made up of trains of repetitive ultrashort laser pulses (microseconds) that create a sublethal cellular thermal effect without heat conduction to adjacent tissue. SDM photocoagulation has been used successfully in the treatment of macular edema in diabetic retinopathy and branch retinal vein occlusion. This is the first report of SDM laser being used for the treatment of CSCR.

In this consecutive case series, 26 eyes in 25 patients with CSCR and juxtafoveal leakage longer than 4 months duration underwent SDM photocoagulation. Eyes were divided into 3 groups based upon fluorescein angiography.

The first group consisted of patients with focal leakage without associated retinal pigment epithelial (RPE) atrophy (N = 6). All 6 of these eyes had total SRF resorption after a single session of SDM photocoagulation.

The second group of eyes were those with point source leakage with associated RPE atrophy (N=9). Eight of 9 eyes had total SRF resorption after 1, 2, or 3 treatment sessions.

The final group had diffuse leakage (N = 11). Only 5 of 11 eyes had SRF resorption at the end of the 6 month follow-up period.

The investigators conclude that SDM laser is effective in the treatment of CSCR with point source leakage. The suggest that PDT may be a better treatment option for eyes with RPE atrophy or diffuse leakage.

WHAT IT MEANS TO YOU: Most patients with CSCR do not requires any treatment, as the condition will usually resolve spontaneously without any residual vision loss. Unfortunately, there are not any good treatment options for patients with chronic recurrent CSCR. Traditional laser therapy has been beneficial for some patients, but carries a risk of residual vision defects due to laser-induced scarring. This new modality of laser therapy may replace traditional laser in those patients that require laser treatment of lesions near the center of the macula.

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Intravitreal Avastin (bevacizumab) administration causes elevation of blood pressure, according to a new research report.

The systemic use of Avastin in cancer treatment has been accompanied by increased incidences of systemic hypertension, but little is known about the systemic effects of intravitreal Avastin. Few systemic side effects have been associated with the intravitreal use of two other anti-VEGF drugs frequently used in the treatment of wet age-related macular degeneration (AMD), Lucentis and Macugen. However, unlike those drugs, Avastin is not approved by the FDA for intravitreal administration, and therefore has not been subjected to the same rigorous safety testing.

The study population consisted of 82 patients with a mean age of 67 years. They were divided into two groups: group A comprised patients who had hypertension and were under medication with antihypertensive drugs; group B comprised patients with normal blood pressure and were not under medication with antihypertensive drugs. All patients were graded according to their blood pressure levels before a single intravitreal dose of Avastin was administered. Blood pressure was again recorded at day 1 and 1, 3, and 6 weeks following the injection.

The researchers found that among persons with hypertension (group A), the systolic blood pressure levels showed significant increases at weeks 1, 3, and 6 compared with baseline. Similarly, diastolic blood pressure levels were significantly higher at weeks 3 and 6. Among persons without high blood pressure (group B), the mean systolic and diastolic blood pressures showed significant elevation only at week 3. The percentages of both group A and B patients with normal blood pressure decreased at week 3 compared with baseline.

The researchers conclude that there is a risk of elevated blood pressure or persistence of hypertension in hypertensive patients after intravitreal Avastin injection.

WHAT IT MEANS TO YOU: It would be wrong to assume that the systemic effects of Avastin will mirror those of Lucentis. The two drugs are similar, but they are not identical. This study demonstrates that inravitreal Avastin may have a clinically significant effect on blood pressure that is not seen with Lucentis, and hence may not be appropriate for some patients.

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pSivida Corp has announced that a clinical trial has begun using its Medidur delivery technology to treat geographic atrophy, the end-stage of dry age-related macular degeneration (AMD). Medidur is a tiny insert designed to be injected intrvitreally. The insert then releases fluocinolone acetonide, a steroid, to the retina for up to three years. The same technology (under the trade name Iluvien) is currently in phase 3 clinical trials for the treatment of diabetic macular edema. "The impetus for this study was the results of experiments conducted in two animal models of retinal degenerations. In both of these models, a miniaturized version of Iluvien demonstrated protective effects on the spontaneous degeneration which occurs in these animals," said Raymond Iezzi, of the Wayne State University School of Medicine. "These results were considered compelling enough to warrant a human study, especially for a condition for which there is no approved treatment," added Dr. Iezzi.

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OPKO Health, Inc. has announced that it has completed enrollment in the company's Phase III clinical trial of bevasiranib for the treatment of wet age-related macular degeneration (wet AMD). The multi-national study has enrolled more than 330 patients and is designed to assess the efficacy and safety of bevasiranib administered every 8 or 12 weeks in preventing vision loss due to wet AMD. Bevasiranib is a first-in-class small interfering RNA (siRNA) drug designed to silence the genes that produce vascular endothelial growth factor (VEGF). VEGF is believed to be largely responsible for the vision loss from wet AMD and bevasiranib is the first drug based on the Nobel Prize-winning RNA interference (RNAi) concept to be in Phase III clinical trials. "This first-ever Phase III trial of an agent based on RNAi technology is a milestone in the field of RNAi," said Phillip Frost, Chairman and CEO of OPKO Health. "With the completion of enrollment, we are one step closer to our goal of submitting a New Drug Application to regulatory agencies worldwide."

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Second Sight Medical Products, the leading developer of retinal prostheses for the blind, announced that it will increase patient enrollment for the Argus II Retinal Implant study in Europe. A three-year feasibility study is currently underway in the United States, Europe and Mexico for people with retinitis pigmentosa (RP). "We are encouraged by the results we have seen in the seventeen individuals that have participated in the study so far," said Robert Greenberg, President and CEO of Second Sight. "We are now expanding our trial enrollment in order to strengthen our data, further demonstrate clinically meaningful performance and begin the process of seeking market approval." Retinal prostheses are currently the only devices being studied to provide some sight to subjects blinded from outer retinal degenerations, such as advanced RP. The Argus II consists of a 60-electrode grid that is surgically implanted on the retina. These electrodes transmit information acquired from an external video camera that is mounted on a pair of eyeglasses worn by implanted subjects.

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