Gene Therapy for Eye Diseases

The pharmaceutical giant Genzyme has started a clinical trial to see whether a drug to treat macular generation could be delivered via long-lasting gene therapy rather than monthly injections.



Eye colors: Drusen, the yellow flecks in this image of the retina, are common in people with age-related macular degeneration. These flecks are made up of proteins involved in the part of the immune system called the complement system, which has also been implicated in the disease by genetic studies.


A drug called Lucentis, made by Genetech, has proved effective at treating the wet form of age-related macular degeneration, which can lead to blindness. Some 200,000 Americans a year are diagnosed with the disease. But Lucentis has to be injected into the eye every month or two, a burden for patients and doctors.
Lucentis binds to and neutralizes a wound-healing growth factor known as VEGF. This binding action stalls the excess growth of blood vessels in the eye that characterizes age-related macular degeneration. Genzyme's gene therapy drug, officially called AAV2-sFLT01, would insinuate itself into the patient's retinal cell to produce the same VEGF-binding protein as Lucentis over far longer periods--up to several years.


A phase 1 clinical trial of Genzyme's gene therapy treatment began at the end of May. Three patients received the treatment, according to Sam Wadsworth, a Genzyme group vice president in charge of gene and cell therapy. Preliminary results should be available in about a year.


The trial is one of a handful worldwide seeking to prove the effectiveness of gene therapy for eye diseases. The Genzyme trial also involves using new type of virus as the delivery mechanism. Early results of a federally funded trial to deliver normal-functioning genes to patients with a rare retinal disease known as type 2 leber congenital amaurosis, or LCA, have confirmed that this "viral vector" has merit for eye treatments, several researchers say.


The LCA trials "demonstrated success both in terms of safety and ability to introduce the gene and have efficacy and success," said Jeffrey S. Heier, an assistant professor at Tufts University School of Medicine and director of retinal research at Ophthalmic Consultants of Boston, a private practice group, who is involved in the Genzyme research. "This study is taking the virus vector that they used, and [Genzyme has] taken what has really been the success of the anti-VEGF story and they've packaged the two together."


Eyes have been an early target for gene therapy because they are small--meaning they require relatively little active dose, they are self-contained, and because the tools of eye surgery have advanced enough to make the treatments possible. The drug has to be delivered to the retina, a thin film lining the inner wall of the eye. Instrumentation has improved in recent years to allow injections through the retina without piercing it, said Shalesh Kaushal, chairman of ophthalmology at University of Massachusetts Memorial Medical Center and UMass Medical School.


To Kaushal, who is involved in the Genzyme study as well as the LCA research, the big challenge will be broadening the use of gene therapy to dozens more diseases, and using that understanding to eventually reach beyond the eye. "If one could understand those fundamental cellular, biochemical events and identify targets, you might have the chance to treat many diseases with a single gene-therapy construct," Kaushal said.


Earlier gene therapy programs used a type of virus called adenovirus to target genes, but both the LCA and Genzyme trials are using adeno-associated virus, which is far less inflammatory and which expresses itself over longer periods than adenovirus, therefore making the treatment last longer, Wadsworth said. Viruses are used to deliver gene therapies because they are adept at getting through cell walls.


VEGF is involved in vascular cell growth throughout the body, and its expression increases in the presence of a wound. Studies have shown that with Lucentis, virtually all the VEGF-binding protein stays within the eye, and does not significantly affect VEGF levels elsewhere in the body, Wadsworth says. Genzyme's drug will provide even lower levels of the VEGF-binding protein, so it's expected that the drug will not have any adverse affects throughout the body, he said.


The trick will be getting the cells to produce enough VEGF-binding protein to help patients, said Peter Campochiaro, a professor at the Wilmer Eye Institute at Johns Hopkins Medicine, who is involved in the research. In addition to establishing safety, the current phase 1 trial will explore four different doses of the study

Tyrosine Kinase inhibitor shows promise for AMD treatment

A new study finds that inhibition of CXCR4 may be useful in preventing neovascularization but does not appear to have an effect on already established angiogenesis, whereas a multiple receptor tyrosine kinase inhibitor (SU14813) reduced the size of previously formed lesions.

Endothelial precursor cells (EPCs) derived from hematopoietic stem cells (HSCs) have been shown to contribute to choroidal neovascularization (CNV) by signaling through the SDF-1 and its receptor, known as CXCR4. Hematopoietic stem cells are implicated in the formation of new pathologic vessels observed in wet AMD. Recruitment of endothelial precursor cells to the site of neovascularization is mediated, in part, by the chemokine SDF-1, and its receptor, CXCR4. CXCR4 is a G-protein-coupled receptor found on lymphocytes, monocytes, hematopoietic, endothelial progenitor cells, and mature endothelial cells.


Methods and Results

CNV in rats was generated by focal rupture of Bruch's membrane with an 810-nm diode laser. In the prevention mode, a CXCR4 antagonist (AMD3100) was delivered via an osmotic pump 1 day after laser induction. In the intervention mode, AMD3100 delivery commenced 14 days after laser induction. Inhibition of CXCR4 was determined through leukocyte and SDF-1 actin polymerization blood biomarker assays. Leakage was assessed by fluorescein angiography, and CNV lesion size was quantified after isolectin B4 endothelial cell staining. SU14813, an anti-VEGFR, PDGFR-beta, KIT, and FLT3 inhibitor, was also assessed in an intervention study protocol.

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Inhibition of CXCR4 was demonstrated by an increase in the number of blood leukocytes, and diminished SDF-1 induced actin polymerization in whole blood. CNV leakage and neovascularization were inhibited when the dose regimen was initiated 1 day after laser-induced CNV induction. AMD3100 did not show efficacy when administered 14 days after lasering. Treatment with SU14813 significantly decreased CNV leakage and lesion size in an intervention modality.

Discussion and Conclusions

In this study, CXCR4 inhibition was efficacious in the prevention of CNV, but failed to reduce choroidal leakage and angiogenesis in the intervention modality. This finding suggests that therapies targeting the SDF-1/CXCR4 axis may be beneficial in blocking the induction of ocular neoangiogenesis, but are unlikely to reduce already established angiogenesis.

There is strong evidence that CXCR4 inhibition disrupts the recruitment of endothelial precursor cells (EPCs) to sites of angiogenesis, most likely the major mechanism leading to efficacy in the prevention model.

In addition to suppressing CNV, CXCR4 inhibition reduced choroidal vascular leakage in the prevention modality (but not in the intervention modality). It is not known whether CXCR4 inhibition decreases leakage directly or as a secondary effect of the reduction of the angiogenic vessel area.

The observation that CXCR4 inhibition did not decrease choroidal leakage or angiogenic lesion size in the intervention modality suggests that after a 2-week generation of laser-induced CNV, there is limited, if any, contribution of EPC cells to the already established vessels

A multiple receptor tyrosine kinase (RTK) inhibitor may still be an effective monotherapy, as SU14813 reduced the size of previously formed lesions. In treatment mode, both leakage and angiogenesis decreased even after the pathologic effect was given 14 days to fully establish before drug intervention. This study suggests that blockade of the VEGF receptor is an effective alternative method of inhibiting the VEGF pathway compared to conventional anti-VEGF strategies.

SU14813 is a small molecule with broad target RTK selectivity, inhibiting the VEGF receptor (VEGFR), PDGFR-β, KIT, and FLT3. Although the primary mechanism that reduces preexisting angiogenesis and leakage is the blockade of the central VEGF pathway, the additional inhibition of PDGFR-β may augment efficacy in this model over single anti-VEGFR agents.

The investigators conclude that inhibition of CXCR4 may be useful in preventing neovascularization but does not appear to have an effect on already established angiogenesis. A multiple receptor tyrosine kinase inhibitor (SU14813) approach shows promise for the treatment of wet age-related macular degeneration.

Finding Macular Degeneration Treatments

Finding macular degeneration treatment s. Vision problems due to the onset of macular degeneration are quite prevalent, especially in the elderly. Macular degeneration occurs when the macula, located in the central portion of the retina in the eye, becomes weakened or damaged. The result is a loss of central vision. Central vision is used to read and drive, so it is crucial to save as much of a patient’s vision as possible as soon as possible. Although this medical condition has no cure at this time, there are some promising new macular degeneration treatments that have shown to alleviate and slow down some of the symptoms of age-related macular degeneration.


There is a range of vision loss that can occur depending on the severity and type of age-related macular degeneration a patient has. Because it affects the macula located in the center of the retina, a patient’s peripheral vision is usually not adversely affected by the condition. With the onset of the condition, a patient’s vision might still be quite good, but the situation can worsen over time. There are two different types of age-related macular degeneration that often result in the greatest loss of central vision, and they are called wet and dry. The dry form of advanced macular degeneration is caused by the reduction of the rods and cones located in the retina, while wet advanced macular degeneration occurs due to leakage of excessive blood vessels and the resulting scarring under the macula.


One thing that retinal specialists might tell their patients with macular degeneration is to take certain vitamins as part of a spectrum of macular degeneration treatment s. Patients in the initial onset stages of this condition sometimes benefit from taking vitamins C, E, zinc, lutein, zeaxanthin and eating foods that are high in beta-carotenes, such as dark green leafy vegetables, corn and peas.


Another macular degeneration treatment can be found in cholesterol reducing drugs. People in the early stages of this medical condition often develop drusen, or yellow deposits, in the macula. The development and increase in the number of drusen seems to be related to the patient’s cholesterol level, with drusen more prevalent in those with higher cholesterol. Medications, such as statins, which reduce cholesterol, and aspirin, which reduces inflammation, may have a significant impact on reducing the size and number of drusen in the macula and thus lessen the chances of someone developing age-related macular degeneration.


A couple of wet advanced macular degeneration treatments, Macugen and Lucentis, have been approved by the FDA. Macugen is useful because it helps to reduce the number of excessive blood vessels that can grow under the retina. These can become inflamed and eventually burst, causing vision problems. Lucentis also reduces the growth of too many blood vessels. Lucentis is administered as an injection under the eye, and offers a great new treatment option for some patients with these kinds of vision problems.


The future is looking brighter with these emerging new macular degeneration treatments.

Susan Slobac has had a parent diagnosed with macular degeneration. She has had experience in macular degeneration treatment. In this article, she discusses macular degeneration risk factors.

For more information follow us at www.maculardegenerationassociation.org

Wider access to drug to prevent and reverse eye damage

By: Staff Writer

Manitobans now have wider access to a drug to prevent and reverse eye damage, Health Minister Theresa Oswald said Wednesday.

The drug Lucentis is now available through doctors' offices to treat wet macular degeneration.

Last March the province said Manitoba Health would cover Lucentis treatment though the Misericordia Eye Centre of Excellence as of June 1.

At that time the province said it wanted to expand patient access to Lucentis through other retinal specialists' offices.

Oswald said Lucentis is now accessible through doctors' offices ahead of schedule.

Wet macular degeneration is a disease that can impair vision and cause blindness.

Lucentis has been available at no cost to Manitobans with wet macular degeneration since June 1 through the Misericordia and Manitoba retinal specialists.

Manitoba Health says up to 1,000 patients could benefit from this new program annually.

Dampening a light-sensing reaction in the eye might slow a common cause of blindness

MIT Technology Review, by Emily Singer - Molecules designed to slow the production of toxic byproducts in the eye by making it less sensitive to light are now being tested in patients with macular degeneration, the leading cause of blindness in people age 50 and older. If successful, the compounds would provide a much needed therapy for the disease, which affects more than 15 million people in the United States.

In macular degeneration, cells in the center of the eye, called the macula, deteriorate. A handful of new treatments for the more severe form of the disease, known as wet AMD, have been approved in recent years. But no treatments are yet available for the dry form, which accounts for about 90 percent of cases. Some dry cases ultimately progress to the wet form, which accounts for a large part of AMD-related blindness. “If you can treat dry AMD, you can kill two birds with one stone,” both reducing early symptoms and preventing progression to the wet form, says Paul Sieving, director of the National Eye Institute, in Bethesda, MD.

While scientists are still trying to understand the causes of AMD–age is the biggest risk factor, with genetics and lifestyle factors also playing a role–a growing pool of evidence suggests that the build up of specific compounds in the eye can hasten the cellular damage that underlies the disease. These compounds accumulate in the photoreceptors–cells in the retina that detect light–during normal eye function as the light-sensitive pigments in these cells change conformation in response to photons.

One form of the photopigment, a derivative of vitamin A, is highly reactive and leaks into nearby tissue called the retinal pigment epithelium. “Over time we think these compounds are a burden for the retinal pigment epithelium, which is essential for the healthy function of the photoreceptors,” says Janet Sparrow, director of the Retinal Cell Biology Laboratory at Columbia University, in New York. “In age-related macular degeneration, particularly the dry form, these cells die, and the photoreceptors follow.”

While this reaction is vital for sight, researchers believe that slowing the cycle in the subset of photoreceptors responsible for night vision, known as rods, could slow damage without having a large impact on daytime vision. (Preliminary results suggest it can affect dark-adaptation–when our eyes adjust to low-light conditions.) “During the daytime, the rods are spinning like crazy, wasting vitamin A for no good use,” says Ryo Kubota, an ophthalmologist and founder of Acucela, a Seattle-based startup that is developing treatments for macular degeneration. “It’s like a CCD camera pointed at the sun.”

One compound developed by Acucela that is in clinical trials inhibits the enzyme that converts the photopigment in photoreceptors from one form to another. This process happens only in the eye, allowing the drug to be administered systemically without affecting other tissue, says Kubota. The company has finished initial safety testing in humans and plans to begin a clinical trial assessing the compound’s effectiveness in patients with late-stage dry macular degeneration in a few weeks. Kubota also aims to test the compound in diabetic retinopathy and Stargardt disease, a rare, genetically inherited form of macular degeneration.

A second drug that acts by a slightly different mechanism is being evaluated for macular degeneration by Sirion Therapeutics, a Florida-based pharmaceutical company. The compound is a synthetic vitamin A derivative that is thought to reduce toxin buildup by binding to one of the proteins involved in the reaction. According to preliminary results from tests of the drug in patients with late-stage dry macular degeneration, it can slow the scarring that is characteristic of the disease by 45 percent. However, scientists won’t know if the results are statistically significant until completion of the study next year. Because no treatments had been approved for dry AMD, in 2009, the U.S. Food and Drug Administration fast-tracked the drug, speeding the review process.

Radiation and Lucentis Combined to Treat Macular Degeneration

by Randall V. Wong M.D

External beam radiation and Lucentis may be combined to treat wet macular degeneration. The results showed the treatment may be very safe and, when combined with anti-VEGF injections such as Lucentis, may decrease the need for frequently repeated injections.

Neovascularization, the growth of abnormal blood vessels, underneath the macular defines “wet macular degeneration.”
Radiation Kills Cells

Radiation treatments have been used in and around the eye to treat tumors. Radiation, in this case, halts the replication of cells. In the case of tumors, the lesions can no longer grow. So too, with neovascularization, new growth is inhibited. This is not the first study that has investigated the use of radiation for wet macular degeneration, but this is one of first trials combining external beam radiation with Lucentis.

Side Effects of Radiation to the Eye

Radiation can be toxic to the eye. It can cause cataracts, damage to the optic nerve and retina. It may also damage the lacrimal (produces tears to the eye) system and cause dry eye.

The investigators were able to dose and administer the radiation safely, seemingly able to avoid the usual complications of external beam radiation.
Treatment Required Fewer Injections of Lucentis

The gold standard for treating wet macular degeneration is now injections with either Lucentis or Avastin. The injections, however, need to be repeated as often as monthly. While highly successful, the need for repeated treatment requires a lot of trips to the office and can be expensive.

The study combined the use of the popular anti-VEGF agent, Lucentis (ranibizumab). The design of the trial required 2 initial injections during the first month of treatment.

52% of patients did not require additional injections for the 12 month study period (they only had 2!).

Also noteworthy, most patients stabilized and actually improved their vision.

What Does This Mean? This is not an approved treatment. It is in no way a true “study,” but this small trial still has some merits. It provides us with a small amount of evidence that alternative treatments using radiation may be useful.

First, recall that anti-VEGF injections, such as Lucentis or Avastin, now standard therapy for wet macular degeneration, were developed for chemotherapy against several types of cancers. The discovery that this improved patients with macular degeneration was coincidental.

For instance, patients receiving chemotherapy for colon cancer started noting improvement in their vision. Evidently, these patients had both cancer and wet macular degeneration.

External beam radiation has long been used for many types of cancer treatments.

In both cases, agents that halt rapidly dividing (i.e. growing) tissues should be effective in both the cancer treatment and the eye disease. The radiation stymies cell replication and the Lucentis (anti-VEGF) inhibits grow of new blood vessels. In the case of cancer, a tumor can not enlarge without blood supply.

So, it makes sense that this may work.

Lastly, this really underscores the need for treatments that do not need to be repeated so frequently, such is the case with Lucentis and Avastin. Right now, most doctors inject as frequently as every 4-6 weeks! Drug delivery systems designed to release drug over an extended period may aid this as well.

Macular Degeneration Wet Treatment

The only way to treat the problem used to be by using a laser, though it has been shown to work only in about half the cases. Now there are chemical and laser-related options, too. Because blood vessel growth is associated with the presence of a ‘vascular endothelial growth factor,’ drugs that impair its function are expected to help. Another solution is to use modified RNA (ribonucleic acid) or sealing blood vessel leaks using lasers. Wet macular degeneration occurs to just 15 per cent of the people with age-related macular problems but are common in two-thirds of the people with a significant loss of vision. In 70 per cent of the cases, wet age-related macular degeneration weakens vision to 20/200 or worse within two years. Antioxidants (including vitamins A, C, and E, selenium, copper, lutein, and zeaxanthine) and zinc have been shown to help preserve vision. And it would help to make full use of vision from outside the central zone, that is, the peripheral vision, to maximum effect. Anti oxidants are known to protect by preventing free oxygen – which is found in high quantities in the blood vessel -rich eye.

For more information go to www.maculardegenerationassociation.org