Friday, September 16, 2011

Treatment can improve vision in macular degeneration

Source: Erin Silversmith, Wikimedia


Macular degeneration is a form of age-related blindness that develops over time. The "wet" form is caused by the growth of new blood vessels in the back of the eye, called neovascularization. The new vessels swell and leak, leading to loss of central vision. VEGF-A (vascular endothelial growth factor-A) has been found to be a key player in the process of angiogenesis, which is necessary for the new vessel growth. Treatments for macular degeneration aim at inhibiting this molecule.

The process of blood vessel growth is called angiogenesis. VEGF-A has been found to play a key role in this process. Thus, inhibiting the actions of this molecule inhibits angiogenesis and prevents neovascularization from proceeding. Antibodies and protein fragments that bind VEGF-A can prevent it from binding its receptor, which prevents it from activating the various chemical pathways that initiate the processes necessary for blood vessel growth. A diagram of the VEGF pathway is available from SA Biosciences. Targeting VEGF-A clearly cuts off the process of angiogenesis at its starting point. Another term for inhibitor is “antagonist”. Thus, VEGF-A antagonists are inhibitors of angiogenesis. The lack of blood vessel growth blocks further neovascularization, reduces vessel leakage, and halts the progression of blindness caused by the abnormal vessels.

However, VAGF-A is involved in both pathological and normal blood vessel growth. In order to limit the actions of the antagonists to VEGF molecules in the affected eye (and ensure the drug reaches the retinal vessels), macular degeneration treatments are injected into the vitreous humor, the jelly-like fluid behind the lens and in front of the retina. Many treatment sessions are needed because the over-expression of VEGF-A is not addressed by the drug – it simply reduces the actions of the VEGF molecules that are present in the eye. Approximately one-half of patients do not improve with treatment, though one type of injection is available that halted the progression of vision loss in 95 percent of patients in clinical trials (specifically, the drug is Lucentis).

According to the American Macular Degeneration Foundation, three anti-VEGF drugs are on the market and used to treat wet macular degeneration. The first to receive FDA approval was pegaptanib (in 2004), which is an RNA aptamer that targets the primary subtype of VEGF-A, known as VEGF 165. However, the first drug approved for treating wet macular degeneration that also improves vision (in approximately 40 percent of patients) is Lucentis (approved in 2006), which contains ranibimuzab, a fragment of a humanized IgGI kappa isotype monoclonal antibody that targets all forms of VEGF-A. Bevacizumab (Avastin) is a full-length humanized monoclonal antibody against VEGF that is used in cancer treatment to prevent angiogenesis, but it is used off label for macular degeneration and not yet approved for such use due to a lack of clinical trials.

Lucentis, and it is the only available treatment that has been shown to potentially restore vision. The drug contains an antibody fragment that binds VEGF-A to prevent it from acting on its receptor. The solution is injected directly into the eye.

Lucentis is marketed by Genentech and was approved by the U.S. Food and Drug Administration (FDA) in 2006 to treat wet macular degeneration Eventually the vessels leak fluid and blood, which causes a blur to appear in, and eventually a loss of, the central vision. Clinical trials of the drug showed that 95 percent of treated patients can expect to experience a halt to the progression of blindness, with approximately 40 percent experiencing improved vision.


In 2010, Lucentis was approved by the FDA to treat retinal vein occlusion, which causes fluid leakage in the eye (also known as macular edema). Both approvals were obtained from the FDA after 6-month priority review, which means that the application was bumped up in the queue due to the planned merits of the drug and the lack of other treatments for the disorder it aims to treat. The FDA offers a full explanation of their fast track approval procedures.


The American Macular Degeneration Foundation notes that Lucentis was the first treatment approved for wet macular degeneration that may actually help patients regain vision. Previous options for patients were laser treatments to halt blood vessel growth and leakage, but the procedure could not reverse the damage to a patient’s vision.


Lucentis contains ranibimuzab, a vascular endothelial growth factor (VEGF) inhibitor. Ranibimuzab is actually an antibody fragment that binds VEGF-A, a form of the growth factor thought to be involved in angiogenesis (new vessel growth) and hyperpermeability (leakiness). Specifically, ranibimuzab is a humanized IgGI kappa isotype monoclonal antibody fragment designed for the interior of the eye (intraocular).


Intravitreal administration, which is injection into the vitreous humor of the eye, the jelly-like solution behind the lens that keeps the retina in place, allows the protein to gain access to the blood vessels of the retina. Lucentis is a sterile, preservative-free solution of the protein fragment in single use vials to avoid bacterial contamination after the first use.


Side effects of the injection include pain and pressure in the eye, increased redness to the whites of the eye, small specks in the patient’s vision, and occasionally sinus or respiratory infection and headache. Serious but rare side effects are inflammation in the eye and cataract formation. The injection should not be given to patients with an infection in or around the eye. If vision worsens, or the eye becomes red, sensitive to light, has a discharge, or the area around the eye swells, the patient should seek medical care from their doctor as a few patients have experienced blood clots and detached retina.

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