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Treating Macular Degeneration with Gene Therapy: New Research Shows Promise but Also Has Limitations

The Lancet logo
The Lancet logo

Currently, there are a number of treatments for wet age-related macular degeneration, including the drugs Lucentis, Eylea, and Avastin, administered by injection with a very small needle directly into the eye after the surface has been numbed (also called "intra-vitreous injection").

There are also a number of treatments that have proven to be inconclusive or unsuccessful after undergoing clinical trials, including stem cells, eye drops, and combination drug treatments.

Most recently, a research team led by Johns Hopkins University School of Medicine is reporting a potentially new approach to the treatment of wet age-related macular degeneration, using gene therapy.

In their research, a virus similar to a cold, but modified in the lab to prevent it from causing disease, is used as a gene carrier and injected into the human eye. This virus, called AAV2, deposits a gene that causes the retinal cells to produce a therapeutic protein called sFLT01, which can halt the creation of abnormal blood vessels.

Please note: Although this very early stage gene therapy research is reported as being safe for humans in a preliminary clinical trial, the research team also states that it may have serious limitations for broader use, due to a built-in immunity to the AAV2 virus in a significant portion of the United States population, as explained below.

From The Lancet

This new macular degeneration gene research, titled Intravitreous injection of AAV2-sFLT01 (explained below) in patients with advanced neovascular [i.e., wet] age-related macular degeneration, has been published in the May 16, 2017 edition of The Lancet.

The Lancet, which has been published continuously for 180 years, is one of the world's leading independent medical journals, without affiliation to a medical or scientific organization. The journal, which is committed to international health concerns, publishes high-quality clinical trials that influence the course of medical practice.

The authors are Jeffrey S Heier, MD; Saleema Kherani, MD; Shilpa Desai, MD; Pravin Dugel, MD; Shalesh Kaushal, MD; Seng H Cheng, PhD; Cheryl Delacono, OD; Annie Purvis, MSPH; Susan Richards, PhD; Annaig Le-Halpere, PharmD; John Connelly, MBA; Samuel C Wadsworth, PhD; Rafael Varona, MD; Ronald Buggage, MD; Abraham Scaria, PhD; and Peter A. Campochiaro, MD, from Johns Hopkins University School of Medicine, Baltimore MD; Ophthalmic Consultants of Boston, Boston, MA; Retinal Consultants of Arizona, Phoenix; University of Massachusetts Medical Center, Worcester, MA; and Sanofi Genzyme, Cambridge, MA.

First, Some Terminology Used in the Research

Here is a brief explanation of some key terms used in this macular degeneration gene research:

  • Gene therapy: A delivery system for drugs. It is a treatment in which genetic material is introduced into cells, either to compensate for an abnormal gene or to create a therapeutic protein, such as AAV2-sFLT01, used in this research.
  • Vector: A "carrier" molecule that transports genetic material into another cell, where it can be reproduced and/or expressed.
  • Adeno-associated virus, or AAV: A virus that infects humans and some other primate species. AAV does not cause disease; instead, it causes a mild immune response.
  • AAV2: A variation of AAV. It is similar to the common cold, altered in the lab so that it does not cause disease. It is used as a carrier, or vector, for a gene and is injected into the eye. The AAV2 virus penetrates retinal cells and deposits the gene, which causes the retinal cells to produce a therapeutic protein called sFLT01.
  • sFLT01: A protein that diminishes the growth of abnormal blood vessels under the retina.
  • Angiogenesis: Describes the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. However, excessive and abnormal blood vessel development can also occur in diseases such as cancer (tumor growth), macular degeneration, and diabetic retinopathy.
  • Neovascularization: When referring to the eye, as in wet age-related macular degeneration, it describes abnormal blood vessel growth in the retina (neo = new; vascular = blood vessels).
  • VEGF: A protein, called vascular endothelial growth factor, that stimulates abnormal blood vessel growth in the retina and macula.

About the Research

Excerpted from New Gene Therapy for Vision Loss Proven Safe in Humans, via Johns Hopkins Medicine:

In a small and preliminary clinical trial, Johns Hopkins researchers and their collaborators have shown that an experimental gene therapy that uses viruses to introduce a therapeutic gene into the eye is safe and that it may be effective in preserving the vision of people with wet age-related macular degeneration (AMD).

The study reports an approach in which a virus, AAV2, which is similar to the common cold but altered in the lab so that it is unable to cause disease, is used as a carrier for a gene and is injected into the eye. The virus penetrates retinal cells and deposits the gene, which turns the cells into factories for productions of a therapeutic protein, called sFLT01.

The phase 1 clinical trial involved 19 men and women, 50 years old or older with advanced wet AMD.

Participants were divided into five different groups that received increasing doses. Each group was examined by investigators for signs of adverse reactions for at least four weeks before administering a higher dose to the next group.

After the virus deposited the gene, the cells began secreting sFLT01 which bound to VEGF and prevented it from stimulating leakage and growth of abnormal blood vessels. The goal is for the retinal cells infected by the virus to produce enough sFLT01 to permanently stop the progression of AMD.

After monitoring the first three groups and finding no dose-limiting toxicity, the researchers administered the maximum dose to a group of ten participants and observed no serious side effects. "Even at the highest dose, the treatment was quite safe. We found there were almost no adverse reactions in our patients," [Study co-author] Peter Campochiaro, MD, says.

[However], five participants showed no reduction in [retinal] fluid levels. Surprisingly, the researchers say, they found that all of the patients who did not show improvement had pre-existing antibodies to the AAV2 virus.

From that result, the researchers conclude that even if further studies affirm the safety and value of their gene therapy, it may have limitations for broad use. That’s because an estimated sixty percent of the U.S. population has been infected with adeno-associated virus, the family of viruses that AAV2 belongs to, and have built an immunity to it. The researchers believe that in these patients, the immune system destroyed the virus before it could insert the therapeutic gene.

Dr. Campochiaro explains, "The numbers are small and simply show a correlation, so we don’t know if serum antibodies are definitely an impediment, but more work is needed to determine this."

More about Wet Age-Related Macular Degeneration

NEI image of how someone with macular degeneration sees: overall blurriness with a blind spot in the center

Seeing the world with AMD

Age-related macular degeneration (AMD) is a gradual, progressive, painless deterioration of the macula, the small sensitive area in the center of the retina that provides clear central vision. Damage to the macula impairs the central (or "detail") vision that helps with essential everyday activities, such as reading and writing, preparing meals, watching television, and personal self-care.

AMD is the leading cause of vision loss for people aged 60 and older in the United States. According to the American Academy of Ophthalmology, 10-15 million individuals have AMD and about 10% of people who are affected have the "wet" type of AMD.

Wet (Neovascular) Macular Degeneration

In wet macular degeneration, the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal blood vessels that develop into a cluster under the macula, called choroidal neovascularization (neo = new; vascular = blood vessels).

The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.

Eylea, Lucentis, Avastin, and Anti-Angiogenic Drugs

retina with wet AMD

A retina with wet AMD

Angiogenesis is a term used to describe the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue.

Sometimes, however, excessive and abnormal blood vessel development can occur in diseases such as cancer (tumor growth) and AMD (retinal and macular bleeding).

Substances that stop the growth of these excessive blood vessels are called anti-angiogenic (anti=against; angio=vessel; genic=development), and anti-neovascular (anti=against; neo=new; vascular=blood vessels).

The focus of current anti-angiogenic drug treatments for wet AMD is to reduce the level of a particular protein (vascular endothelial growth factor, or VEGF) that stimulates abnormal blood vessel growth in the retina and macula; thus, these drugs, including Lucentis, Avastin, and Eylea, are classified as anti-VEGF treatments. These drugs are administered by injection with a very small needle directly into the eye after the surface has been numbed.

About Clinical Trials

Most clinical trials are designated as Phase 1, 2, or 3, based on the questions the study is seeking to answer:

  • In Phase 1 clinical trials, researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe and effective dosage range, and identify possible side effects.
  • In Phase 2 clinical trials, the study drug or treatment is given to a larger group of people to determine if it is effective and to further evaluate its safety.
  • In Phase 3 studies, the study drug or treatment is given to even larger groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
  • In Phase 4 studies, after the United States Food and Drug Administration (FDA) has approved the drug, continuing studies will determine additional information, such as the drug's risks, side effects, benefits, and optimal use.

More About the Study from The Lancet

Excerpted from the study Abstract:

Background: Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralizing proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralizing protein sFLT01 in patients with advanced neovascular age-related macular degeneration.

Methods: This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrollment, with the first three patients being assigned to, and completing, the first cohort before filling positions in the following treatment groups.

Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (or groups) and one maximum tolerated dose cohort and followed up for 52 weeks.

The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events.

Interpretation: Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Additional studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies.

VisionAware will continue report on this, and other, genetic research as results become available.

Additional Information About Macular Degeneration


Topics:
Avastin
Clinical Trials
Eylea
Gene Therapy
Low Vision
Lucentis
Macular Degeneration
Medical Updates

New Genetic Research in Diabetes Identifies a Protein That May Stop or Reduce Abnormal Blood Vessel Growth in the Retina

retina with diabetic retinopathy

A retina with diabetic
retinopathy

New genetic research in diabetes, led by a team from Harvard Medical School, has identified a potential new therapy targeting RUNX1 (explained below) that significantly reduced abnormal blood vessel growth in the retina, which is a hallmark of advanced diabetic eye disease.

Although the research has been conducted only with "in vitro" (explained below) laboratory studies of human retinal cells and mouse retinas, the study authors are "hopeful" that inhibiting RUNX1 may also help manage abnormal retinal blood vessel growth in a number of other eye conditions – such as wet macular degeneration and retinopathy of prematurity – earlier in the disease process, before the abnormal blood vessels have a chance to develop.

"We're hopeful that we may have an opportunity to change the treatment paradigm for these conditions," said co-author Leo A. Kim, M.D., Ph.D. "Instead of treating patients after these abnormal blood vessels form in the eye, we may be able to give patients eye drops or systemic medications that prevent their development in the first place."

The Research from Diabetes

This new diabetes research, titled Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis (Translation: Identification of a protein that can change or reduce the abnormal blood vessel growth that occurs in retinal disease, including diabetic retinopathy), has been published "online first" on April 11, 2017, in Diabetes, published by the American Diabetes Association. Diabetes presents original research about the normal and abnormal physical processes that occur with diabetes mellitus, including laboratory, animal, and human research.

The authors are Jonathan D. Lam, Daniel J. Oh, Lindsay L. Wong, Dhanesh Amarnani, Cindy Park-Windhol, Angie V. Sanchez, Jonathan Cardona-Velez, Declan McGuone, Anat O. Stemmer-Rachamimov, Dean Eliott, Diane R. Bielenberg, Tave van Zyl, Lishuang Shen, Xiaowu Gai, Patricia A. D'Amore, Leo A. Kim, and Joseph F. Arboleda-Velasquez, from Harvard Medical School, Boston, MA; Massachusetts General Hospital, Boston, MA; Children's Hospital Los Angeles, Los Angeles, CA; and Universidad Pontificia Bolivariana, Medellin, Colombia.

First, Some Terminology Used in the Research

Here is a brief explanation of some key terms used in this diabetes research:

  • Angiogenesis: Describes the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. However, excessive and abnormal blood vessel development can also occur in diseases such as cancer (tumor growth), macular degeneration, and diabetic retinopathy (retinal and macular bleeding).
  • In vitro: Refers to processes taking place in a test tube or culture dish, typically in a laboratory. "In vivo" refers to processes taking place in a living human or other organism.
  • Neovascularization: When referring to the eye, as in diabetic retinopathy and wet age-related macular degeneration, it describes abnormal blood vessel growth in the retina (neo = new; vascular = blood vessels). Neovascularization is also a feature of other eye and health conditions, including retinopathy of prematurity and cancer.
  • RUNX1: Runt-related transcription factor 1, a protein that in humans is encoded by the RUNX1 gene. The RUNX1 protein activates genes that help control the development of blood cells.
  • VEGF: A protein, called vascular endothelial growth factor, that stimulates abnormal blood vessel growth in the retina and macula.

About the Research

Excerpted from Researchers identify new target for abnormal blood vessel growth in the eyes, via Medical Xpress:

[Researchers] have identified a novel therapeutic target for retinal neovascularization, or abnormal blood vessel growth in the retina, a hallmark of advanced diabetic eye disease (proliferative diabetic retinopathy).

… the transcription factor RUNX1 was found in abnormal retinal blood vessels, and by inhibiting RUNX1 with a small molecule drug, the researchers achieved a 50 percent reduction of retinopathy in preclinical [meaning before human clinical trials have begun] models. These findings pave the way for new therapies that address diabetic retinopathy and other conditions involving abnormal vessel growth within the retina.

"Current treatments to control retinal neovascularization require injecting very large proteins [i.e., Lucentis, Eylea, and Avastin] … into the eyes of patients, as often as once a month. Our study opens the door for novel modes of treatment based on small molecules that could cross biological barriers on their own. Such a treatment could be self-administered by patients and eliminate the need for intravitreal injections," said co-author Joseph F. Arboleda-Velasquez, M.D., Ph.D.

In the Diabetes report, the authors studied tissue from patients with proliferative diabetic retinopathy. They identified the presence of RUNX1 in the diseased blood vessels but not in the normal blood vessels. Next, they used a small molecule drug originally developed as a cancer therapy to inhibit the activity of RUNX1 in the eye, which led to a significant reduction of abnormal blood vessels.

The study authors are hopeful that inhibiting RUNX1 may present a more targeted opportunity for managing the retinopathy of certain eye conditions—perhaps earlier in the disease process, before the abnormal blood vessels develop. Future studies will test whether the drug can be delivered through topical eye drops rather than by injection, and further explore the relationship between RUNX1 and VEGF, as these factors seemingly both play a role in angiogenesis.

More about Diabetic Eye Disease

Diabetic Retinopathy

Although people with diabetes are more likely to develop cataracts at a younger age and are twice as likely to develop glaucoma as people who do not have diabetes, the primary vision problem caused by diabetes is diabetic retinopathy, the leading cause of new cases of blindness and low vision in adults aged 20-65:

NEI example of seeing with diabetic retinopathy: many blind spots and overall blurriness

How a person with
diabetic retinopathy might see

  • "Retinopathy" is a general term that describes damage to the retina.
  • The retina is a thin, light-sensitive tissue that lines the inside surface of the eye. Nerve cells in the retina convert incoming light into electrical impulses. These electrical impulses are carried by the optic nerve to the brain, which interprets them as visual images.
  • Diabetic retinopathy occurs when there is damage to the small blood vessels that nourish tissue and nerve cells in the retina.
  • "Proliferative" is a general term that means to grow or increase at a rapid rate by producing new tissue or cells. When the term "proliferative" is used in relation to diabetic retinopathy, it describes the growth, or proliferation, of abnormal new blood vessels in the retina. "Non-proliferative" indicates that this process is not yet occurring.
  • Proliferative diabetic retinopathy affects approximately 1 in 20 individuals with the disease.

Four Stages of Diabetic Retinopathy

According to the National Eye Institute, diabetic retinopathy has four stages:

  • Mild non-proliferative retinopathy: At this early stage, small areas of balloon-like swelling occur in the retina's tiny blood vessels.
  • Moderate non-proliferative retinopathy: As the disease progresses, some blood vessels that nourish the retina become blocked.
  • Severe non-proliferative retinopathy: Many more blood vessels become blocked, which disrupts the blood supply that nourishes the retina. The damaged retina then signals the body to produce new blood vessels.
  • Proliferative retinopathy: At this advanced stage, signals sent by the retina trigger the development of new blood vessels that grow (or proliferate) in the retina and the vitreous, which is a transparent gel that fills the interior of the eye. Because these new blood vessels are abnormal, they can rupture and bleed, causing hemorrhages in the retina or vitreous. Scar tissue can develop and can tug at the retina, causing further damage or even retinal detachment.

You can learn more about all current treatments for diabetic retinopathy at What Treatments Are Available for Diabetic Eye Disease? at VisionAware.org

More About the Study from the Journal Diabetes

Excerpted from the study Abstract:

Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population, and affects those with type 1 and type 2 diabetes mellitus.

We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+ vascular endothelial cells obtained from human PDR fibrovascular membranes (FVM) via transcriptomic analysis.

In vitro studies using human retinal microvascular endothelial cells (HRMECs) [i.e., cells on the inner lining of blood vessels] showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation.

Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVM and angiogenic tufts in the retina of mice with oxygen-induced retinopathy (OIR), suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis.

Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy (OIR), supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.

Additional Diabetes Information


Topics:
Diabetes and diabetic retinopathy
In the News
Macular Degeneration
Medical Updates
Gene Therapy

Is It Possible to Identify and Treat Cell Damage from Glaucoma Much Earlier in the Course of the Disease? New Research Says Maybe

a view of the retina to check for glaucoma

Glaucoma often is called "the sneak thief of sight" for good reason: Many people are unaware that glaucoma has few symptoms or warning signs in its early stages. Early treatment for glaucoma can sometimes (but not always) slow the progression of the disease. However, as of yet, there is no cure for glaucoma.

Now, researchers from Washington University School of Medicine in St. Louis have identified a biomarker (explained below) that seems to be linked to cell damage in the eye from glaucoma. According to study co-author Rajendra S. Apte, M.D., Ph.D., "We've identified a biomarker that seems to correlate with disease severity in patients, and what that marker is measuring is stress to the cells rather than cell death. Other glaucoma tests are measuring cell death, which is not reversible, but if we can identify when cells are under stress, then there's the potential to save those cells to preserve vision."

Please note that this glaucoma research is in its very earliest stages, has been conducted thus far primarily with laboratory mice, and will require many more years of testing with human subjects. Nevertheless, this concept shows promise for developing future glaucoma treatments to detect optic nerve changes at an earlier stage and initiate treatments much earlier in the disease process.

From the Journal JCI Insight

This new glaucoma research, titled GDF15 (explained below) is elevated in mice following retinal ganglion cell death and in glaucoma patients, has been published in the May 4, 2017 edition of JCI Insight, a new open-source peer-reviewed journal launched by the American Society for Clinical Investigation and the Journal of Clinical Investigation. JCI Insight is dedicated to biomedical research, ranging from preclinical to clinical studies.

The authors are Norimitsu Ban, Carla J. Siegfried, Jonathan B. Lin, Ying-Bo Shui, Julia Sein, Wolfgang Pita-Thomas, Abdoulaye Sene, Andrea Santeford, Mae Gordon, Rachel Lamb, Zhenyu Dong, Shannon C. Kelly, Valeria Cavalli, Jun Yoshino, and Rajendra S. Apte, from Washington University in St. Louis School of Medicine, St. Louis, Missouri.

First, An Explanation of Terms Used in the Research

Here is a brief explanation of some key terms used in this glaucoma research:

  • Biomarker: A substance in the body that can be measured and whose presence indicates disease, infection, or environmental exposure. Biomarkers are measured and evaluated to examine normal body processes, disease processes, or responses to drugs used in a therapeutic intervention.
  • GDF15: Growth differentiation factor 15 (GDF15) is a protein that responds to stress within the body – in this case, the optic nerve. It plays a role in regulating inflammation and cell death in body tissues that are injured by disease.
  • Retinal ganglion cells: Neurons, or nervous system cells. They are located near the inner surface of the retina and give rise to optic nerve fibers that transmit information from the retina to several regions in the brain.

About the Glaucoma Predictor Research

Excerpted from Potential Predictor of Glaucoma Damage Identified, via Newswise:

Studying mice, rats, and fluid removed from the eyes of patients with glaucoma, researchers at Washington University School of Medicine in St. Louis have identified a marker of damage to cells in the eye that potentially could be used to monitor progression of the disease and the effectiveness of treatment.

Glaucoma is the second-leading cause of blindness in the world, affecting more than 60 million people. The disease often begins silently, with peripheral vision loss that occurs so gradually that it can go unnoticed. Over time, central vision becomes affected, which can mean substantial damage already has occurred before any aggressive therapy begins.

Many patients start receiving treatment when their doctors discover they have elevated pressure in the eye. Those treatments, such as eye drops, are aimed at lowering pressure in the eye, but such therapies may not always protect ganglion cells in the retina, which are the cells destroyed in glaucoma, leading to vision loss.

Co-author Rajendra S. Apte says that all current treatments for glaucoma are aimed at lowering pressure in the eye to reduce ganglion cell loss and not necessarily at directly preserving ganglion cells.

Studying mouse models of glaucoma, [the researchers] identified a molecule in the eye called growth differentiation factor 15 (GDF15), noting that the levels of the molecule increased as the animals aged and developed optic nerve damage. When they repeated the experiments in rats, they replicated their results. Further, in patients undergoing eye surgery to treat glaucoma, cataracts and other issues, the researchers found that those with glaucoma also had elevated GDF15 in the fluid of their eyes.

"That was exciting because comparing the fluid from patients without glaucoma to those with glaucoma, the GDF15 biomarker was significantly elevated in the glaucoma patients," Apte said. "We also found that higher levels of the molecule were associated with worse functional outcomes, so this biomarker seems to correlate with disease severity."

A potential limitation of this study is that the fluid samples were taken from the eyes of patients only once, so it was not possible to monitor levels of GDF15 over time. In future studies, it will be important to measure the biomarker at several time points to determine whether levels of the biomarker increase as the disease progresses, Apte said.

What Is Glaucoma?

Glaucoma is a group of eye diseases that can lead to blindness by damaging the optic nerve, which transmits information from the eye to the brain, where it is processed and interpreted. The eye continuously produces a fluid, called the aqueous, that must drain from the eye to maintain healthy eye pressure. Glaucoma is particularly dangerous to your vision because there are usually no noticeable initial symptoms or early warning signs.

The Different Types of Glaucoma

Primary Open Angle Glaucoma

The most common type of glaucoma is Primary Open Angle Glaucoma (POAG). In POAG, the eye's drainage canals become blocked, and the fluid accumulation causes pressure to build within the eye. This pressure can cause damage to the optic nerve, which transmits information from the eye to the brain.

Vision loss is with this type of glaucoma is usually gradual, and often there are no early warning signs. There is a strong genetic predisposition for this type of glaucoma.

Angle Closure Glaucoma

Angle Closure Glaucoma is much less common than POAG in the United States. In this type of glaucoma, the aqueous cannot drain properly because the entrance to the drainage canal is either too narrow or is closed completely. In this case, eye pressure can rise very quickly and can be triggered by pupil dilation.

Symptoms can include sudden eye pain, nausea, headaches, and blurred vision. If you experience these symptoms, you should seek immediate medical treatment.

Normal Tension Glaucoma

In this type of glaucoma, also called low-pressure glaucoma, there is damage to the optic nerve, even though the eye pressure is not elevated excessively. A family history of any type of glaucoma, cardiovascular disease, and Japanese ancestry are a few of the risk factors for this type of glaucoma.

This type of glaucoma is treated much like POAG, but the eye pressure needs to be kept even lower to prevent progression of vision loss.

Secondary Glaucomas

Secondary glaucomas are those that develop as secondary to, or as complications of, other conditions, including eye trauma, cataracts, diabetes, eye surgery, or tumors.

Series of four photos demonstrating typical progression of vision loss due to glaucoma. Source: National Eye Institute

The typical progression of vision loss from glaucoma
Source: National Eye Institute

Detecting Glaucoma

Because glaucoma has no obvious initial symptoms, a comprehensive dilated eye exam is critical to detect early glaucoma changes. People who are over 40 should have a dilated eye examination from an ophthalmologist or optometrist at least every two years. African Americans; people who are over 35 and have a family history of glaucoma; and everyone age 60 or older should schedule a comprehensive eye examination every year.

You can learn more about glaucoma detection and treatment at How Can I Detect Glaucoma if There Are No Initial Symptoms?, What Are the Different Treatments for Glaucoma?, and Tips for Taking Glaucoma (and Other) Eye Drops at VisionAware.

More About the Glaucoma Detection Research from JCI Insight

Here is more information about the study, excerpted from the article Abstract and Introduction, with the full article available online:

Glaucoma is the second leading cause of blindness around the world. It is a group of … diseases characterized by neuroretinal degeneration associated with death of retinal ganglion cells (RGCs), which in turn leads to optic neuropathy. In glaucoma, progressive optic neuropathy, if left untreated, leads to visual field (VF) defects that may ultimately result in irreversible blindness.

Numerous factors — including genetics and race, as well as ocular characteristics such as intraocular pressure (IOP) and central corneal thickness — have been identified as risk factors in the development and progression of glaucoma. Currently, all medical and surgical therapies for glaucoma focus on lowering IOP as a strategy to protect RGCs from cell death.

Although neuroprotection for glaucoma would be highly desirable, therapeutic strategies that have focused on neuroprotection have thus far failed to demonstrate efficacy in clinical trials, with no agents currently approved by regulatory authorities.

Another impediment for effective glaucoma treatment is the paucity of molecular markers that predict progression of glaucomatous neurodegeneration that results in optic neuropathy. Treating physicians have generally relied on VF testing, IOP measurement, and optic nerve monitoring as metrics for assessing whether disease is adequately controlled.

However, the nature of VF testing, lack of precise correlation of IOP with disease risk, and lack of validated normative databases for optic nerve imaging techniques, such as optical coherent tomography (OCT), contribute to the persistent challenges of glaucoma management.

Of significant concern, these evaluations presently form the basis for treatment decisions regarding additional medical and surgical interventions to prevent disease progression and vision loss. Therefore, there is an acute need to identify specific molecular markers that quantify glaucomatous neurodegeneration by accurately and objectively measuring RGC-specific cell death.

In this study, we have, to our knowledge, characterized in mice and rats a novel molecular marker of glaucomatous neurodegeneration. We have further validated our findings in human glaucoma patients with varying degrees of disease severity. These results highlight a protein with potential use as a marker of glaucomatous neurodegeneration.

Additional Glaucoma Information


Topics:
Glaucoma
In the News
Medical Updates

May Is Healthy Vision Month: Make Your Eye Health a Priority and Learn How to Protect Your Vision

Healthy Vision 2017 logo

May is Healthy Vision Month, a national eye health observance established by the National Eye Institute (NEI) in May 2003. NEI is part of the National Institutes of Health, an agency of the United States Department of Health and Human Services.

This year, NEI is encouraging women to make eye health a priority and has designated four women as ambassadors – including VisionAware's Audrey Demmitt – who share their experiences with eye health and their tips on making eye health a priority. You can read Audrey's story on the Healthy Vision Month Ambassadors page.

As part of Healthy Vision Month, NEI also provides information about a number of steps all Americans can take to protect our eyes and vision:

  • Get a comprehensive dilated eye exam.
  • Know your family history, including any family history of eye problems.
  • Wear sunglasses. Sunglasses help protect your eyes from ultraviolet (UV) rays. Prolonged exposure to sunlight can increase your risk of cataracts and macular degeneration. When buying sunglasses, look for those that block out 99 to 100 percent of both UVA and UVB rays.
  • Use protective eyewear. Protect your eyes when doing household chores or yardwork, playing sports, or working on the job. Wear safety glasses, goggles, shields, or eye guards made of polycarbonate. Talk with your eye care provider about the right kind of protective eyewear for your needs.
  • Live a healthy lifestyle, including eating healthy foods; maintaining a healthy weight; managing chronic conditions, such as diabetes; and refraining from smoking.

According to NEI, "Taking these steps can help prevent vision loss or blindness from many eye diseases and conditions, including macular degeneration, cataracts, and glaucoma. In addition, comprehensive dilated eye exams can detect problems early, when they're easier to treat." You can learn more about the steps to take to protect your vision at Keeping Your Eyes Healthy at NEI's Healthy Vision Month website.

What Is a Comprehensive Dilated Eye Examination?

A comprehensive dilated eye examination generally lasts between 30 and 60 minutes, and is performed by an ophthalmologist or optometrist. It should always include the following components:

1. A Health and Medication History

  • Your overall health and that of your immediate family
  • The medications you are taking (both prescription and over-the-counter)
  • Questions about high blood pressure (hypertension), diabetes, smoking, and sun exposure.

2. A Vision History

  • How well you can see at present, including any recent changes in your vision
  • Eye diseases that you or your family members have had, including macular degeneration and glaucoma
  • Previous eye treatments, surgeries, or injuries
  • The date of your last eye examination

As part of the vision history, the doctor may ask you the following questions:

  • Are you having any problems with your vision?
  • How long have you had these problems?
  • When do these problems occur?
  • When was your last eye examination?
  • Do you have any family history of eye problems?
  • How is your general health?
  • What medications are you taking?
  • Do you have any allergies?

This history of your own health and that of your family can give the doctor an indication of any issues that may be affecting, or could affect, your vision.

3. An Eye Health Evaluation

  • An examination of the external parts of your eyes: the whites of the eyes, the iris, pupil, eyelids, and eyelashes.
  • A dilated eye examination that uses special lenses that allow your doctor to see inside your eye and examine the retina and optic nerve. Your doctor might choose to use eye drops to see the retina and optic nerve more clearly.
  • A test of the fluid pressure within your eyes to check for the possibility of glaucoma.

4. A Refraction, or Visual Acuity Testing

a phoropter

A refraction helps determine the sharpness or clarity of both your near (reading) and distance vision.

This includes testing your vision with different lenses (sometimes contained in a machine called a phoropter, pictured at right) to determine if your vision can be improved or corrected with regular glasses or contact lenses.

5. Visual Field Testing

Visual field testing helps determine how much side (or peripheral) vision you have and how much surrounding area you can see.

Humphrey Field Analyzer

The most common type of visual field test in a comprehensive eye exam is called a confrontation field test, in which the doctor briefly flashes several fingers in each of the four quadrants (above, below, right, and left) of your visual field while seated opposite you.

In some cases, your doctor may also want to perform a more precise visual field measurement, using a computerized visual field analyzer, such as the Humphrey Field Analyzer (pictured at left).

6. Your Examination Results

The doctor will be able to determine if the visual problems you are experiencing are normal age-related changes or are disease-related, and if additional testing, referral to another doctor or specialist, or treatments are needed. You can read more at The Difference Between a Vision Screening and a Comprehensive Eye Examination at VisionAware.

Wearing Absorptive Sunglasses

Glare can be a major problem and concern for many persons. Absorptive sunglasses help filter out bothersome glare and harmful light rays. Most sunglasses now block out ultraviolet light. However, to block out "blue" light, which causes concern for macular degeneration and other eye conditions, sunglasses need to have some amount of yellow in them.

The colors of sunglasses that contain some yellow and block out blue light are amber, orange, amber/orange combination, plum, and yellow. Grey and green-grey colored sunglasses do not block out any blue light. Grey and green-grey sunglasses also do not provide as good contrast as do amber, orange, plum, and yellow.

absorptive lenses in amber fit over regular eyeglasses

Absorptive sunglasses
in amber fit over
regular eyeglasses

Some advantages of absorptive sunglasses are:

  • They can reduce bothersome glare, enhance or clarify vision in the sunlight, ease eye fatigue, and protect the eyes from injuries, such as walking into a low-hanging branch.
  • They block out harmful light rays. Most block out ultraviolet (UV) light, while amber, orange, plum, and yellow-colored sunglasses also block out blue light.
  • Amber, orange, plum, and yellow-colored sunglasses also help enhance or increase contrast.
  • Yellow-colored sunglasses are helpful for use indoors (reading, writing, doing handicrafts, using a computer) to reduce glare and enhance contrast.
  • They are generally inexpensive and easy to obtain.
  • They can be fitted over regular glasses, and they are available in clip-on or insert styles.
  • Please note: Clip-ons and inserts are usually not as effective as fit-over or wrap-around styles, since they do not block light from the top and sides.
  • It is recommended that you try on a range of colors and styles during the low vision examination to determine which color or colors work best for you.

You can read more at Helpful Non-Optical Devices for Low Vision at VisionAware.

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The FDA Approves Lucentis for the Treatment of Diabetic Retinopathy

retina with diabetic retinopathy

A retina with diabetic
retinopathy

On April 17, 2017, the United States Food and Drug Administration (FDA) granted approval to the injectable drug Lucentis (generic name ranibizumab) for the treatment of proliferative diabetic retinopathy (PDR), a serious vision-related complication of diabetes.

Previously, the FDA approved Lucentis for the treatment of diabetic macular edema (DME), a buildup of fluid in the macula, the center of the retina. Thus, with this latest treatment advance and FDA approval, physicians can use Lucentis to manage diabetic retinopathy in people with or without diabetic macular edema.

Important Background On this Research from The Journal of the American Medical Association

Results from an important clinical trial revealed that the injectable drug Lucentis is highly effective in treating proliferative diabetic retinopathy, a serious vision-related complication of diabetes.

The research, titled Panretinal Photocoagulation [i.e., laser treatment] vs Intravitreous Ranibizumab [i.e., Lucentis injection] for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial, was published online as an open-source article in the November 13, 2015 edition of The Journal of the American Medical Association and was timed to coincide with a presentation by the study authors at the 2015 Annual Meeting of the American Academy of Ophthalmology. The authors are the members of the Writing Committee for the Diabetic Retinopathy Clinical Research Network.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a collaborative research group that supports the identification, design, and implementation of multi-center clinical research studies focused on diabetes-related eye and retinal disorders, including diabetic retinopathy and diabetic macular edema. The DRCR.net was formed in September 2002 and currently includes over 115 participating sites with over 400 physicians throughout the United States. It is funded by the National Eye Institute (NEI).

"These findings," said Dr. Paul Sieving, Director of the National Eye Institute (NEI), "provide crucial evidence for a safe and effective alternative to laser therapy against proliferative diabetic retinopathy." The clinical trial was funded by NEI, which described Lucentis as the first major advance in therapy for proliferative diabetic retinopathy in nearly 40 years. Although longer-term follow-up will be needed, Lucentis may provide a reasonable treatment alternative, at least through two years, for persons with proliferative diabetic retinopathy.

About Diabetic Eye Disease and Diabetic Retinopathy

Although people with diabetes are more likely to develop cataracts at a younger age and are twice as likely to develop glaucoma as people who do not have diabetes, the primary vision problem caused by diabetes is diabetic retinopathy, the leading cause of new cases of blindness and low vision in adults aged 20-65:

NEI example of seeing with diabetic retinopathy: many blind spots and overall blurriness

What a person with diabetic retinopathy sees

  • "Retinopathy" is a general term that describes damage to the retina.
  • The retina is a thin, light-sensitive tissue that lines the inside surface of the eye. Nerve cells in the retina convert incoming light into electrical impulses. These electrical impulses are carried by the optic nerve to the brain, which interprets them as visual images.
  • Diabetic retinopathy occurs when there is damage to the small blood vessels that nourish tissue and nerve cells in the retina.
  • "Proliferative" is a general term that means to grow or increase at a rapid rate by producing new tissue or cells. When the term "proliferative" is used in relation to diabetic retinopathy, it describes the growth, or proliferation, of abnormal new blood vessels in the retina. "Non-proliferative" indicates that this process is not yet occurring.
  • Proliferative diabetic retinopathy affects approximately 1 in 20 individuals with the disease.

Four Stages of Diabetic Retinopathy

According to the National Eye Institute, diabetic retinopathy has four stages:

  • Mild non-proliferative retinopathy: At this early stage, small areas of balloon-like swelling occur in the retina's tiny blood vessels.
  • Moderate non-proliferative retinopathy: As the disease progresses, some blood vessels that nourish the retina become blocked.
  • Severe non-proliferative retinopathy: Many more blood vessels become blocked, which disrupts the blood supply that nourishes the retina. The damaged retina then signals the body to produce new blood vessels.
  • Proliferative retinopathy: At this advanced stage, signals sent by the retina trigger the development of new blood vessels that grow (or proliferate) in the retina and the vitreous, which is a transparent gel that fills the interior of the eye. Because these new blood vessels are abnormal, they can rupture and bleed, causing hemorrhages in the retina or vitreous. Scar tissue can develop and can tug at the retina, causing further damage or even retinal detachment.

In addition, fluid can leak into the macula, the small sensitive area in the center of the retina that provides detail vision. This fluid can cause macular edema (or swelling), which can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses.

Lucentis: An Anti-Angiogenic Drug to Treat Retinal Bleeding

Angiogenesis is a term used to describe the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. Sometimes, however, excessive and abnormal blood vessel development can occur in diseases such as cancer (tumor growth) and retinal disease.

Substances that stop the growth of these excessive blood vessels are called anti-angiogenic (anti=against; angio=vessel; genic=development), and anti-neovascular (anti=against; neo=new; vascular=blood vessels).

The focus of current anti-angiogenic drug treatments for retinal disease is to reduce the level of a particular protein (vascular endothelial growth factor, or VEGF) that stimulates abnormal blood vessel growth in the retina and macula; thus, these drugs are classified as anti-VEGF treatments and are administered by injection directly into the eye after the surface has been numbed.

At present, these anti-VEGF drugs (Lucentis, Avastin, and Eylea) require monthly injections or a pro re nata [meaning "as needed"] (PRN) regimen, with monthly controls and injections for recurrent or persistent blood vessel growth and retinal bleeding.

More about Lucentis and Diabetic Retinopathy Research

Excerpted from Lucentis proves effective against proliferative diabetic retinopathy, via Science Codex:

A clinical trial among more than 300 patients has found that the drug ranibizumab (Lucentis) is highly effective in treating proliferative diabetic retinopathy (PDR), a complication of diabetes that can severely damage eyesight. The results demonstrate the first major therapy advance for the condition in nearly 40 years.

The trial compared Lucentis injections with a type of laser therapy called panretinal photocoagulation, which has remained the gold standard for PDR since the mid-1970s. Although laser therapy preserves central vision, it can damage night and side vision, so researchers have sought therapies that lack these side effects.

"Patients who received Lucentis showed a little bit better central vision, much less loss of their side vision, and substantially less risk for surgery than patients who received laser treatment," said Lloyd Paul Aiello, M.D., Ph.D., director of the Beetham Eye Institute at Joslin Diabetes Center and Professor of Ophthalmology at Harvard Medical School. "These findings will change the available treatment options for patients with PDR."

The DRCR.net enrolled 305 participants (394 eyes) with PDR in one or both eyes at 55 clinical sites across the country. Eyes were assigned randomly to treatment with Lucentis or laser. About half of the eyes assigned to the laser group required more than one round of laser treatment. In the other group, Lucentis was injected into the eye once per month for three consecutive months, and then as needed until the disease resolved or stabilized.

Because Lucentis is commonly injected to treat diabetic macular edema (DME) – a build-up of fluid in the center of the retina – the study permitted the use of Lucentis for DME in the laser group, if necessary. Slightly more than half (53 percent) of eyes in the laser group received Lucentis injections to treat DME. About 6 percent of eyes in the Lucentis group received laser therapy, mostly for issues other than DME.

At two years, vision in the Lucentis group improved by an average of about half a line on an eye chart, compared with virtually no change in the laser group. Participants treated with laser generally lost substantial peripheral vision, but those given injections did not. Additionally, the need for vitrectomy surgery was lower in the Lucentis group (8 of 191 eyes) than in the laser group (30 of 203 eyes).

Overall, the drug's benefits are particularly clear for people with both PDR and DME. "We know that this drug will help treat both conditions at the same time, so this is an especially appealing treatment alternative for these patients," Dr. Aiello noted.

The study also suggested that Lucentis may help prevent DME. Among people without this condition at the start of the study, only 9 percent of Lucentis-treated eyes developed it, compared with 28 percent in the laser group. Scientists will follow up on that result as the DRCR.net continues to track patients for a total of five years.

More about the Study from The Journal of the American Medical Association

Excerpted from the article abstract, with the full article available online:

Importance: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME).

Objective: To evaluate the non-inferiority of intravitreous ranibizumab [i.e., Lucentis injections] compared with [laser] for visual acuity outcomes in patients with proliferative diabetic retinopathy.

Design, Setting, and Participants: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.

Interventions: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n=203 eyes), or [Lucentis], 0.5 mg, by intravitreous [i.e., within the eye] injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n=191 eyes). Eyes in both treatment groups could receive [Lucentis] for DME.

Main Outcomes and Measures: The primary outcome was mean visual acuity change at 2 years (5-letter non-inferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.

Results: Mean visual acuity letter improvement at 2 years was +2.8 in the [Lucentis] group vs +0.2 in the PRP group. The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2. Mean peripheral visual field sensitivity loss was worse, vitrectomy was more frequent, and DME development was more frequent in the [laser] group vs the [Lucentis] group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different. One eye in the [Lucentis] group developed endophthalmitis [i.e., an inflammation of the eye, usually caused by infection]. No significant differences between groups in rates of major cardiovascular events were identified.

Conclusions and Relevance: Among eyes with proliferative diabetic retinopathy, treatment with [Lucentis] resulted in visual acuity that was non-inferior to (not worse than) [laser] treatment at 2 years. Although longer-term follow-up is needed, [Lucentis] may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.

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