Possible new treatment for Macular Degeneration

Researchers from University of Kentucky College of Medicine have identified an RNA-based mechanism in the retina that could be responsible for triggering the blindness associated with advanced dry age-related macular degeneration (AMD). The article has been published in Nature.

Unlike wet AMD, which results from scarring caused by leaky blood vessels and thus can be treated with a variety of angiogenesis inhibitors, dry AMD is initially characterized by the buildup of extracellular debris beneath the retina. Over time, those deposits cause significant atrophy of the retinal pigment epithelial (RPE) layer—a condition known as geographic atrophy—leading to loss of photoreceptors in the macula, the central and the most important part of the retina, which can ultimately advance to permanent blindness.

Although difficult to predict, dry AMD can turn into wet AMD at any time during disease progression. There are no medical or surgical treatments for dry AMD.

To find potential targets for geographic atrophy, Dr Jayakrishna Ambati and colleagues initially looked at levels of proteins and nucleic acids in eye samples from dry AMD patients. The researchers found that levels of the microRNA-processing enzyme dicer 1 ribonuclease type III (DICER1) were significantly lower in patient eyes than in non-AMD control eyes (p=0.0036). DICER1 levels were unchanged in the RPE layer of human eyes with other retinal diseases, suggesting that low DICER1 could be a specific marker of geographic atrophy.

The team next generated Dicer1 knockout mice to recapitulate the geographic atrophy phenotype in animals. All the Dicer1 knockouts showed degeneration of the RPE layer compared with wild-type littermate controls.

Subsequent studies in human RPE cells and mice revealed the specific mechanism by which low DICER1 levels led to degeneration of the RPE cells or layer, respectively. The decrease in DICER1 caused the accumulation of cytotoxic Alu RNA molecules in the RPE layer, where they caused degeneration of tissues making up the retina and macula.

Alu RNAs are retrotransposon sequences that exist throughout the human genome but do not code for proteins. Considered to be a toxic type of RNA that play a disease-causing role in a large section of the human genome, these Alu-related elements make up 11 percent of the human genome. They were considered "junk" DNA because researchers did not understand their role, but are now considered to play a crucial role in the death of retinal cells in those with geographic atrophy

In cultured human RPE cells with low DICER1 levels, antisense oligonucleotides targeting Alu RNA significantly blocked RPE cellular degeneration compared with control oligonucleotides (p<0.05).

Simply said, in patients with geographic atrophy, reduction of the Dicer enzyme in the retina leads to accumulation of Alu RNA, which leads to death of the retina.

The team has also developed two therapies that may prevent geographic atrophy. The first therapy increases Dicer levels in the retina by "over-expressing the enzyme", while the second therapy blocks Alu RNA with a drug that clings to the toxic structure and degrades it. Based on experiments performed in the laboratory, both therapies could efficiently prevent geographic atrophy.

The University of Kentucky has filed for patents on both therapies, and clinical trials are expected to begin by the end of this year.

Comparison of Avastin versus Lucentis for treatment of wet type of Age-Related Macular Degeneration Treatments (CATT trial)

People with vascular diseases of the retina, such as age-related macular degeneration (AMD), diabetic macular edema, vascular occlusions like the central retinal vein occlusion, even retinopathy of prematurity (ROP) have been offered treatment in the form of injections of Ranibizumab (trade name Lucentis)or Bevacizumab (trade name Avastin) into the eye every few weeks. These injections control the expression of vascular endothelial growth factor (VEGF), which is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. When VEGF is overexpressed, it can contribute to disease.

Genentech, a wholly owned susdiary of the Swiss pharmaceutical conglomerate Hoffmann-La Roche [], developed Lucentis, which is a monoclonal antibody fragment (Fab) derived from the same parent murine antibody as Avastin. It is much smaller than the parent molecule, and has a stronger binding to VEGF-A. This feature gives it anti-angiogenic properties, which has helped it get regulatory approval in many countries around the world to treat wet AMD, which is a common form of age-related vision loss. It is marketed in the United States by Genentech and elsewhere by Novartis. Avastin, developed specifically for use in colorectal cancers, was found to be useful in the eye for AMD as well. With a significant cost difference between Avastin at an average cost of $42 a dose (in the U.S.) versus Lucentis at an average cost of $1,593 a dose, there was a difference of opinion between retina specialists and those who marketed the drug, with the specialists claiming that the effect from both appeared to be equal, while the latter claimed they were not responsible for any untoward side-effects from the use of off-lable Avastin in the eye.

With an on-going debate that showed no signs of resolution, a clinical trial comparing the two treatments in patients with wet AMD (CATT) was planned to effectively answer the question whether Lucentis has any potential benefit over Avastin.

In a multicenter, single-blind, noninferiority trial, 1208 patients with neovascular (or wet) AMD were randomly assigned to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.

The study group recently reported its result in the New England Journal of Medicine, with the conclusion that Avastin administered monthly or as needed was equivalent to Lucentis administered monthly or as needed respectively. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, p = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (p>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with Avastin than with Lucentis (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66).

So the major conclusion from this CATT study is that at the end of 1 year, Avastin and Lucentis had equivalent effects on visual acuity when administered according to the same schedule. The authors mention that the differences in rates of serious adverse events require further study. (The study was funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.)

p.s. In this continuing saga of Lucentis versus Avastin, New York Times reports that Genentech has been  offering secret rebates to eye doctors as an apparent inducement to get them to use more of the company’s expensive drug Lucentis rather than a less costly alternative.

Gene therapy shows promise against age-related macular degeneration

According to Tufts news, a gene therapy approach using a protein called CD59, or protectin, shows promise in slowing the signs of age-related macular degeneration (AMD). A new in vivo study conducted by researchers at Tufts University School of Medicine led by Rajendra Kumar-Singh, PhD, has demonstrated for the first time that CD59 delivered by a gene therapy approach significantly reduced the uncontrolled blood vessel growth and cell death typical of AMD,which is the most common cause of blindness in the elderly.

Activation of the complement system, a part of the immune system, is responsible for slowly killing cells in the back of the eye, leading to AMD. Activation of this system leads to the generation of pores or holes known as 'membrane attack complex' or MAC in cell membranes. CD59 is known to block the formation of MAC.

Previous studies using CD59 have have had limited success, as CD59 is considered to be unstable. By continuously producing CD59 in the eye. the approach by these investigators is able to overcome these barriers, which increases hope that it can be used to fight the progression of AMD as well as other diseases.

Kumar-Singh is associate professor in the department of ophthalmology at Tufts University School of Medicine (TUSM) and member of the genetics; neuroscience; and cell, molecular, and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Kumar-Singh and colleagues delivered CD59 to the eye using a deactivated virus similar to one previously shown to be safe in humans. Using an established mouse model of age-related macular degeneration, they found that eyes treated with CD59 had 62 percent less uncontrolled blood vessel growth and 52 percent less MAC than controls.

Source

For those who want to read the scientific article, please click here.