VisionAware Blog

Track This Blog By E-mail

Clinical Trial Update: Squalamine Eye Drops for Wet Macular Degeneration

Photograph of a retina with wet age-related macular degeneration

A retina with wet AMD

Many readers have been following closely the development of Squalamine Eye Drops for wet age-related macular degeneration, hoping that a self-administered at-home eye drop could reduce, or even eliminate, the need for monthly or as-needed eye injections. Unfortunately, a clinical trial designed to test this concept has produced disappointing results: Squalamine Eye Drops failed to reduce the average number of Lucentis injections required by the trial participants.

However, that clinical trial also revealed that squalamine produced positive changes in visual acuity – both overall in the Lucentis/squalamine treatment group, and, more significantly, in participants with a specific type of AMD lesion. Therefore, a newer clinical trial, initiated in 2016 and continuing into 2019, will continue to study the effects of Squalamine Eye Drops, in combination with Lucentis injections, on gains in visual acuity in persons with wet macular degeneration.

What is Squalamine?

Ohr Pharmaceutical, Inc. is dedicated to the clinical development of new drugs for underserved therapeutic needs. One of its lead drugs in development is Squalamine Eye Drops for the treatment of wet age-related macular degeneration (AMD).

Squalamine is a water-soluble molecule derived from the internal organs (primarily the liver) of the dogfish shark. It is believed to have great potential for treating some human viruses. Medically, squalamine has been shown to interrupt and reverse the process of angiogenesis.

About Angiogenesis and Anti-Angiogenic Drugs

Angiogenesis is a term that describes the growth of new blood vessels and plays a critical 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 macular degeneration 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.

The squalamine researchers theorized that the ability to self-administer eye drops to treat wet AMD could be more effective (and less invasive) than the current standard of care, which involves regular injections of Lucentis, Avastin, or Eylea directly into the eye, via a very small needle. These injections are administered at the doctor's office.

A History of Squalamine Eye Drop Research

Initially, the Genaera Corporation developed the squalamine project and administered squalamine as an intravenous formulation for wet AMD in Phase 1 and Phase 2 clinical trials. However, in 2007, Genaera discontinued their clinical trials, due to financial and subject-recruitment issues. The squalamine project was then acquired by Ohr Pharmaceutical, which continued the development of squalamine in a topical eye drop formulation.

In 2012, Ohr was awarded "Fast Track" designation by the United States Food and Drug Administration (FDA) to further develop its Squalamine Eye Drop product for the potential treatment of wet AMD. Fast Track is a process designed to facilitate the development, and expedite the review, of drugs to treat serious diseases and fill an unmet medical need. Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy that may be potentially superior to existing therapy.

The Phase 2 Clinical Trial

In August 2012, the FDA commenced a Phase 2 clinical trial to study the safety and effectiveness of Squalamine Eye Drops in combination with Lucentis injections. The researchers were seeking to determine (a) if squalamine was safe (safety) and (b) if Squalamine Eye Drops could reduce the number and frequency of Lucentis injections required to control the neovascularization and retinal bleeding associated with wet AMD (effectiveness).

The initial enrollment in the clinical trial was 142 "treatment-naïve" participants [i.e., meaning that no participant had received prior treatments] at 23 clinical ophthalmology centers across the United States. 128 participants completed the study.

All participants in the nine-month study received an initial injection of Lucentis to begin and then were randomly assigned to receive either Squalamine Eye Drops [i.e., the treatment group] or placebo eye drops twice a day throughout the study. [Editor's note: A placebo is an inactive substance that has no therapeutic effect, used as a control in testing new drugs.]

All participants were seen monthly during the study period and received eye examinations, visual acuity testing, and optical coherence tomography (OCT) testing. Additional Lucentis injections were given on an as-needed basis to control the new blood vessel development and retinal bleeding associated with wet AMD. [Editor's note: Optical coherence tomography (OCT) is a type of medical imaging technology that produces high-resolution cross-sectional and three-dimensional images of the eye. It is used to gain a clearer picture of the retina and its supporting layers.]

You can learn more about the Phase 2 squalamine clinical trial, including criteria for enrollment and the locations of the clinical trial study centers, at Efficacy and Safety of Squalamine Eye Drops at ClinicalTrials.gov.

The Clinical Trial Results

Safety: Squalamine Eye Drops were well-tolerated. Only two participants in the treatment group discontinued the study, due to eye pain or swelling.

Effectiveness: Unfortunately, Squalamine Eye Drops failed to decrease the average number of Lucentis injections required by the study participants. This was the primary goal of the clinical trial and the result was disappointing, both to researchers and to people with wet AMD, who were hoping that Squalamine Eye Drops could possibly reduce, or even eliminate, the need for eye injections.

There Were Some Positive Results from the Phase 2 Clinical Trial

the ETDRS chart

The Early Treatment of Diabetic Retinopathy Study (ETDRS) Chart

Despite not reaching the study's primary end goal, there were additional results from the Phase 2 clinical trial that may be encouraging. Although Squalamine Eye Drops did not reduce the need for, or the frequency of, eye injections, squalamine did produce positive changes in visual acuity, or clearness of vision – both overall in the Lucentis/squalamine treatment group, and more significantly, in participants with a specific type of AMD lesion.

31% of the study participants who received the combined Lucentis/squalamine treatment gained 3 or more letters on the Early Treatment of Diabetic Retinopathy Study (ETDRS) Eye Chart (pictured at left), versus 25% of participants who received Lucentis treatment alone (meaning the Lucentis/placebo treatment).

However, 37 participants with "classic" AMD lesions who received the combined Lucentis/squalamine treatment gained 11 letters on the ETDRS Eye Chart, versus 5 letters with Lucentis treatment alone. Classic AMD lesions have also shown benefit in other studies of combined treatment.

A Phase 3 Clinical Trial Is Now Underway

Due to these gains in vision from the study's combination therapy, Ohr has moved forward with a Phase 3 clinical trial. The two-year trial, which commenced in 2016, will enroll 650 participants and is estimated to be completed in mid-2019. It will continue to study the effects of Squalamine Eye Drops in combination with Lucentis injections, versus Lucentis injections alone, on best-corrected visual acuity.

VisionAware will provide updates of this ongoing macular degeneration clinical trial as they become available.

Additional Information about Macular Degeneration


Topics:
Avastin
Clinical Trials
Eylea
In the News
Low Vision
Lucentis
Macular Degeneration
Medical Updates

New Research: Ebola Survivors Have Ongoing Risk of Eye Disease, Even When the Initial Outbreak Has Concluded

Cover of the journal Ophthalmology

Although worldwide attention was focused on the 2014-2016 Ebola outbreak in West Africa, considerably less attention – until now – has been paid to the eye and vision complications resulting from the disease. This month, a group of researchers from the United States, Liberia, and Uganda have published data describing the ocular findings, visual impairment, and associated complications of Ebola in a group of survivors in Monrovia, Liberia.

They conclude that "survivors of Ebola virus disease (EVD) are at risk for uveitis (explained below), which may lead to eye damage, visual impairment, and blindness. Eye care resources should be mobilized for EVD survivors throughout West Africa, who are at ongoing risk of uveitis and severe vision loss, although the acute EVD outbreak has concluded."

From the Journal Ophthalmology

This new Ebola/eye disease research, titled Ophthalmic Manifestations and Causes of Vision Impairment in Ebola Virus Disease Survivors in Monrovia, Liberia, has been published online ahead of print in the December 2016 edition of Ophthalmology, the official journal of the American Academy of Ophthalmology. Ophthalmology publishes original, peer-reviewed research in ophthalmology, including new diagnostic and surgical techniques, the latest drug findings, and results of clinical trials.

The authors are Jessica G. Shantha, MD; Ian Crozier, MD; Brent R. Hayek, MD; Beau B. Bruce, MD, MPH; Catherine Gargu; Jerry Brown, MD; John Fankhauser, MD; and Steven Yeh, MD, who represent the following organizations and institutions: Emory University School of Medicine and Emory University, Atlanta, Georgia; the Infectious Diseases Institute, Kampala, Uganda; the Ministry of Health and Sanitation, Monrovia, Liberia; and Eternal Love Winning Africa Hospital, Monrovia, Liberia.

About the Ebola and Uveitis Research

Edited and excerpted from Vision impairment and eye diseases continue to be concerns for Ebola survivors, via Medical Xpress:

The acute outbreak of Ebola virus disease (EVD) has subsided in West Africa, but the medical community continues to learn about long-term complications for survivors – including the potential for blinding eye disease. One particular condition of concern is uveitis.

Uveitis refers to inflammation of the eye, which can lead to problems ranging from mildly reduced vision to severe vision loss and blindness. Patients with uveitis can experience eye redness, blurred vision, eye pain, headache and/or sensitivity to light.

The [study] reports on nearly 100 EVD survivors in Monrovia, Liberia. Liberia, along with Sierra Leone and Guinea, were the three countries most affected by the 2014 EVD outbreak. More than 10,000 cases of EVD were reported in Liberia alone during the recent outbreak; over 28,000 cases were reported during the West African EVD outbreak between 2013 and 2016.

Of the 96 patients examined, 21 had developed an EVD-associated uveitis and three developed an EVD-associated optic neuropathy [i.e., damage to the optic nerve]. In addition, nearly 40 percent of the patients with uveitis were legally blind. Other findings include cataract and [floaters/flashes of light], which can both be complications of untreated uveitis.

"These findings have implications from medical and surgical perspectives, particularly given our prior finding of live Ebola virus in the ocular fluid of a recovered Ebola survivor," said [study co-author] Steven Yeh, MD.

The public health risk in these cases lies in knowing what kinds of precautions health care workers should take when treating Ebola survivors who develop cataracts.

What is Ebola Virus Disease?

From the World Health Organization (WHO) Ebola key facts:

  • Ebola virus disease (EVD), formerly known as Ebola hemorrhagic [i.e., bleeding, both internally and externally] fever, is a severe, often fatal illness in humans.
  • The virus is transmitted to people from wild animals and spreads in the human population through human-to-human transmission.
  • The average EVD case fatality rate is around 50%. Case fatality rates have varied from 25% to 90% in past outbreaks.
  • The first EVD outbreaks occurred in remote villages in Central Africa, near tropical rainforests, but the most recent outbreak in West Africa has involved major urban as well as rural areas.
  • Community engagement is key to successfully controlling outbreaks. Good outbreak control relies on applying a package of interventions, namely case management, surveillance and contact tracing, a good laboratory service, safe burials, and social mobilization.
  • Early supportive care with rehydration, and [treatment of symptoms] improves survival.
  • There is as yet no licensed treatment proven to neutralize the virus, but a range of blood, immunological, and drug therapies are under development.
  • There are currently no licensed Ebola vaccines but two potential candidates are undergoing evaluation.

You can read more about Ebola transmission, symptoms, diagnosis, treatment, prevention, and controlling infection in health-care settings at Ebola virus disease: Fact sheet from WHO.

What is Uveitis?

an eye with anterior uveitis

An eye with anterior uveitis

Uveitis (you-vee-EYE-tis) is an internal inflammation of the eye, involving the middle layers of the eye, also called the uveal tract. The uveal tract contains veins and arteries that transport blood to the parts of the eye that are critical for vision:

  • Ciliary body: Contains the ciliary muscles, which change the lens shape and curvature, and the ciliary processes, which produce aqueous humor, a clear, watery fluid that provides nutrients to all parts of the eye.
  • Iris: A tissue inside the eye that has a hole in the center, forming the pupil. The iris contains muscles that allow the pupil to become larger (open up or dilate) and smaller (close up or constrict). The iris regulates the amount of light that enters the eye by adjusting the size of the pupil opening. The iris also determines eye color.
  • Choroid: A dark brown membrane that is rich with blood vessels. It supplies blood and nutrients to the retina and nourishes all other structures within the eye.

Uveitis has many potential causes, including inflammatory disease affecting other parts of the body; a viral infection; bacteria; a fungal infection; a parasite, or an injury to the eye. Symptoms of uveitis include eye redness and irritation; blurred vision; eye pain; and increased sensitivity to light.

Complications of uveitis can include glaucoma; cataracts; abnormal growth of blood vessels in the eyes that interfere with vision; fluid within the retina; and vision loss. Early diagnosis and treatment is critical. See New Research: Uveitis, an Inflammatory Eye Disease, May Signal the Onset of Multiple Sclerosis for other potential complications.

More about the Ebola Study from Ophthalmology

From the study summary and abstract:

Purpose: To describe the ocular findings, visual impairment, and association of structural complications of uveitis with visual impairment in a cohort of survivors of Ebola virus disease (EVD) in Monrovia, Liberia.

Participants: Survivors of EVD who were evaluated in an ophthalmology clinic at Eternal Love Winning Africa (ELWA) Hospital in Monrovia, Liberia.

Methods: A cohort of EVD survivors who underwent baseline ophthalmic evaluation at ELWA Hospital were retrospectively [i.e., examining data and records that were collected in the past] reviewed for demographic information, length of Ebola treatment unit (ETU) stay, visual acuity (VA), and ophthalmic examination findings. For patients with uveitis, disease activity (active vs. inactive) and grade of inflammation were recorded according to Standardization of Uveitis Nomenclature criteria.

The level of VA impairment was categorized according to World Health Organization classification as follows: normal/mild, VA 20/70 or better; moderate, VA 20/70–20/200; severe, VA 20/200–20/400; blindness, VA less than 20/400. Visual acuity, length of ETU stay, and structural complications were compared between EVD survivors with and without uveitis. Structural complications associated with moderate VA impairment or poorer were analyzed.

Results: A total of 96 survivors of EVD were examined. A total of 21 patients developed an EVD-associated uveitis, and 3 patients developed an EVD-associated optic neuropathy. Visual acuity was blind in 38.5% of eyes with uveitis. Examination findings associated with at least moderate visual impairment by World Health Organization criteria (VA less than 20/70) included keratic precipitates [i.e., inflammatory deposits on the cornea]; posterior synechiae [i.e., the iris adhering to the lens]; vitritis [i.e., inflammation of the vitreous]; and chorioretinal scars [i.e., scarring or inflammation of the choroid and retina].

Conclusions: Survivors of EVD are at risk for uveitis, which may lead to secondary structural complications, visual impairment, and blindness. Eye care resources should be mobilized for EVD survivors in West Africa because of the frequency of this spectrum of disease complication and its potential for severe VA impairment and blindness.

Additional Information at VisionAware


Topics:
Cultural Diversity
Education
Health
In the News
Low Vision
Medical Updates
Public Policy

New Glaucoma Research from the United Kingdom: Could a Glaucoma Treatment also Help Prevent Alzheimer's Disease?

 logo for Glaucoma Awareness Month

Two recent United Kingdom-based eye research projects have begun to explore potential (but not yet proven) links between retinal disease and beta-amyloid proteins that accumulate in the brains of people with Alzheimer's disease.

The first project, from the University of Southampton, England, investigated the potential role of beta-amyloid protein in the development of macular degeneration.

The second project (explained below), from researchers at University College London (UCL), used mouse models to determine that the drug brimonidine, routinely used to lower glaucoma eye pressure, also reduced the formation of beta-amyloid proteins in the retina, which are linked to Alzheimer's disease.

According to study co-author Francesca Cordeiro, M.D., Ph.D., "The findings of our study could not have come at a more significant and important moment, given the increased prevalence of Alzheimer’s disease. As we live longer, there will be increasing demand for therapies that can help challenge this extremely damaging disease and we believe that our findings can make a major contribution.

Please note that this research does not indicate that macular degeneration or glaucoma can result from Alzheimer's disease, or that one condition can contribute to the development of the other. What the research does indicate, however, is that studying the behavior of beta-amyloid proteins can provide insight into Alzheimer's disease and the retinal damage that accompanies macular degeneration and glaucoma.

From Cell Death & Disease

This new glaucoma research examining the potential role of beta-amyloid protein has been published in the December 2016 edition of Cell Death & Disease, part of the Nature Group of scientific journals that seeks to promote "areas of experimental and internal medicine within its specialties, including cancer, cancer metabolism, immunity, and neuroscience."

The authors are Shereen Nizari, Li Guo, Benjamin M. Davis, Eduardo M. Normando, Joana Galvao, Lisa A. Turner, Mukhtar Bizrah, Mohammad Dehabadi, Kailin Tian, and M. Francesca Cordeiro, from University College London (UCL) Institute of Ophthalmology; and the Western Eye Hospital, Imperial College Healthcare Trust, London, United Kingdom.

What is Beta-Amyloid?

In its most basic form, beta-amyloid (BAY-tuh AM-uh-loyd) is a single protein fragment, snipped from a larger protein found in the fatty membrane surrounding nerve cells. Because it is chemically "sticky," these protein fragments tend to clump or cluster, gradually building into hard, insoluble "plaques" in the brain that are one of the hallmarks of Alzheimer's disease. As they cluster, these beta-amyloid plaques erode synapses, which are the connections between nerve cells that help to conduct nerve impulses. Synapses are essential in encoding, consolidating, storing, and retrieving memories.

Please note, however, that there is much still unknown about beta-amyloid, including its role in Alzheimer's disease, as illustrated by the discouraging results of a recent clinical trial for an experimental drug targeting amyloid buildup. According to the New York Times,

An experimental Alzheimer's drug that had previously appeared to show promise in slowing the deterioration of thinking and memory has failed in a large Eli Lilly clinical trial, dealing a significant disappointment to patients hoping for a treatment that would alleviate their symptoms.

The failure of the drug, solanezumab, underscores the difficulty of treating people who show even mild dementia, and supports the idea that by that time, the damage in their brains may already be too extensive. And because the drug attacked the amyloid plaques that are the hallmark of Alzheimer's, the trial results renew questions about a leading theory of the disease, which contends that it is largely caused by amyloid buildup.

About the Glaucoma/Amyloid Research

Excerpted from Glaucoma drug may have potential to treat Alzheimer's disease, via UCL News:

A drug which is used to treat the common eye disease glaucoma may have potential as a treatment for Alzheimer’s disease, according to scientists at UCL.

In trials on rats, the drug brimonidine, which is routinely used to lower eye pressure in glaucoma patients, has been found to reduce the formation of amyloid proteins in the retina, which are believed to be linked to Alzheimer's.

Amyloid plaques can be seen in the retinas of people with Alzheimer's, so the researchers say the retina can be viewed as an extension of the brain that provides an opportunity to diagnose and track progression of Alzheimer's.

Scientists found that brimonidine reduces [the degeneration of nerve cells] in the retina by cutting the levels of beta-amyloid in the eye. This was achieved by using the drug to stimulate the production of an alternative non-toxic protein which does not kill nerve cells.

The researchers hope that the drug will have a similar effect on the brain, although this was not tested in the current study.

What Is Brimonidine?

Brimonidine (brand names Alphagan and Alphagan-P) is a drug that is used in an eye drop formulation to treat open-angle glaucoma and ocular hypertension. It decreases intraocular [i.e., within the eye] pressure by reducing the production of aqueous humor and increasing the outflow of the aqueous fluid. You can learn more about the full range of treatments for glaucoma at What Are the Different Treatments for Glaucoma? at VisionAware.

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

National Glaucoma Awareness Month provides a perfect opportunity to learn more about glaucoma, a leading cause of vision loss that affects more than 3 million people in the United States. 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 usually (but not always) slow the progression of the disease. However, as of yet, there is no cure for 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 Study from Cell Death & Disease

First, here is a brief explanation of some key terms used in the research:

  • Retinal ganglion cells (RGCs): 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.
  • Amyloid precursor protein: Plays an essential role in nerve growth and repair. However, later in life, a corrupted form can destroy nerve cells, leading to the loss of thought and memory in Alzheimer's disease.
  • Neuroprotective: Protecting nerve cells from damage, degeneration, or impairment of function.
  • Neurodegeneration: Degeneration of the nervous system, especially of neurons in the brain.
  • In vivo: Processes taking place in a living organism.
  • In vitro: Processes or reactions taking place in a test tube, culture dish, or elsewhere outside a living organism.

Excerpted from the study (and simplified for non-scientist readers), with the full article available online:

Glaucoma is a major cause of visual impairment worldwide and is characterized by optic neuropathy [i.e., optic nerve damage] and visual field loss. Retinal ganglion cell death is considered an early hallmark of glaucoma and raised intraocular pressure (IOP) is presently the only modifiable risk factor. As a proportion of glaucoma patients continue to lose vision despite effective IOP control, IOP-independent risk factors are increasingly thought to have a role in glaucoma pathology.

Amyloid beta, the major constituent of senile plaques in Alzheimer's disease, has recently been implicated in glaucoma pathology. Amyloid beta is associated with abnormal processing of amyloid precursor protein.

Using rodent glaucoma models, the pathway of amyloid deposit formation has recently been identified as a target for the development of novel neuroprotective glaucoma therapies. Here, amyloid beta deposits were found to induce retinal ganglion cell death, a finding supported by a study on glaucoma patients reporting reduced amyloid beta concentrations in the vitreous. Amyloid beta may therefore be important in the stress–response to glaucoma neurodegeneration and offers a novel therapeutic target.

Brimonidine, an alpha adrenergic receptor agonist was introduced as an IOP-lowering agent; however, increasing experimental evidence suggests it also has IOP-independent neuroprotective activity.

The present study confirms the neuroprotective actions of alpha adrenergic receptor agonists, using in vivo and in vitro models of retinal neurodegeneration with a novel IOP-independent mechanism of action. This mechanism proposes that a reduction in retinal ganglion cell death is achieved through reduced amyloid beta production, and its amyloid precursor protein.

The applications of alpha adrenergic receptor agonists may therefore not be limited to reducing retinal ganglion cell death in glaucoma, but also to any neurodegenerative process where amyloid beta nervous system damage is involved, such as Alzheimer's disease. This work strongly advocates investigation of the therapeutic potential of alpha adrenergic receptor agonists in these disorders.

More Information

For more detailed and patient-centered glaucoma information, see Discovering the Sneak Thief: Diagnosing Glaucoma in VisionAware's Patient's Guide to Living with Glaucoma and El descubrimiento del ladrón silencioso: El diagnóstico de glaucoma in Guía del Paciente: Vivir con Glaucoma.


Topics:
Glaucoma
Health
In the News
Macular Degeneration
Medical Updates
Aging
Low Vision

January Is National Glaucoma Awareness Month: Learn More About Glaucoma and Current Treatments

 logo for Glaucoma Awareness Month

National Glaucoma Awareness Month provides a perfect opportunity to learn more about glaucoma, a leading cause of vision loss that affects more than 3 million people in the United States. 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 usually (but not always) slow the progression of the disease. However, as of yet, there is no cure for 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.

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

How Is Glaucoma Detected?

Because glaucoma can begin to develop without noticeable symptoms, the best way to protect your sight is to schedule regular comprehensive dilated eye examinations, which should include all of the following components:

  • A health and medication history
  • A vision history
  • Visual acuity testing
  • Basic visual field testing

You can read more about each of these eye examination components at What Is a Comprehensive Dilated Eye Examination?

Additional Tests for Glaucoma

If your eye doctor suspects that you may have glaucoma, you will need to undergo additional testing that can help your doctor make a more definitive glaucoma diagnosis:

Pachymetry

  • This test uses a probe that emits an ultrasonic wave to measure the thickness of your cornea. Thicker than normal corneas can give eye pressure readings that are inaccurately high, while thinner than normal corneas can give readings that are inaccurately low.
  • To measure your corneal thickness, the doctor will touch the tip of the pachymeter probe to the surface of your cornea. The probe emits a painless ultrasound wave that measures your corneal thickness. The doctor will numb the surface of your eye with an anesthetic drop for this test.

Perimetry

  • This test measures and maps your visual fields. Perimetry testing can draw a map of your visual fields and show you where you may have lost vision, especially your peripheral (or side) vision, which is the vision usually affected by early damage to the optic nerve from glaucoma.
the Humphrey Field Analyzer
  • The most commonly used test for perimetry is the Humphrey Field Analyzer (pictured at left). The machine resembles a large bowl.
  • One eye is covered with a patch and the other eye remains stationary and focused straight ahead. Small white lights of varying sizes and intensities will flash at different locations around the bowl. You will be instructed to press a button whenever you see a flashing light.
  • By recording which lights you see and which ones you do not, it creates a map of your visual field.

Gonioscopy

  • This test assesses the angle, or drainage canal, that is formed between your cornea and iris. Because angle-closure glaucoma requires immediate medical attention, it is important to examine the drainage canals, or angles, to ensure that they are functioning properly.
  • Because the drainage angle is located around a "corner" of your cornea, the doctor can't see whether your angle is open by looking directly into your eye.
  • Gonioscopy uses a lens with a mirror to view the angle. During the exam, the doctor places this lens, called a gonioscope, on the surface of your eye like a large contact lens. The doctor will numb the surface of your eye with an anesthetic drop for this test.

For more detailed and patient-centered information about ophthalmoscopy, tonometry, pachymetry, perimetry, and gonioscopy, see Discovering the Sneak Thief: Diagnosing Glaucoma in VisionAware's Patient's Guide to Living with Glaucoma and El descubrimiento del ladrón silencioso: El diagnóstico de glaucoma in Guía del Paciente: Vivir con Glaucoma.

What Is the Treatment for Glaucoma?

Glaucoma is a chronic condition that must be monitored for life. With proper monitoring and compliance with treatment, glaucoma can be managed – but not cured. Current treatments include eye medications, laser treatment, surgery, and several newer surgical alternatives.

Eye Medications

For tips, adaptations, and assistive devices to help you take your glaucoma medications, see Tips for Taking Glaucoma (and Other) Eye Drops by Ira Marc Price, O.D.

Laser Treatment

If eye drop medications do not adequately control your glaucoma, the next step is a treatment called a laser trabeculoplasty. In this procedure, laser energy is directed at the trabecular meshwork, which is the drainage system of the eye. The laser treatment lowers pressure by increasing the drainage of the fluid from the eye. The procedure is relatively short, painless, and usually performed in the doctor's office.

Three types of lasers can be used for the procedure:

  • Argon laser trabeculoplasty (ALT) has been used for more than two decades.
  • Selective laser trabeculoplasty (SLT)
  • Micropulse laser trabeculoplasty (MLT)
  • SLT and MLT are two newer laser treatments now available.
  • Side effects from all types of lasers include mild inflammation in the eye and a possible temporary pressure rise. A short course of a mild steroid or non-steroidal anti-inflammatory eye drop is used to treat any resulting inflammation.
  • Other lasers are available, but these are reserved for people with particular types of glaucoma that narrow or completely close the drainage system of the eye.

Surgery

Surgery to treat glaucoma is usually undertaken only as a final step for people who have not achieved adequate pressure control with either eye drop medications or laser treatment.

Depending on the type of glaucoma and associated risk factors, two types of surgeries are available:

  • Filtering Surgery: Trabeculectomy: In a trabeculectomy, a small incision is made in the sclera (the white of the eye). Fluid slowly leaks from this incision into a "bleb," which is a covered space made in the conjunctiva (the thin, transparent tissue that covers the outer surface of the eye). The fluid in the bleb is slowly reabsorbed by the eye. This surgery provides a "natural" alternate drainage for aqueous to flow out of the eye.
  • Drainage Device Surgery: Drainage device surgery partially inserts an artificial tube implant into the eye. Fluid drains through the tube and out to a reservoir. This surgery provides an "artificial" alternate drainage for aqueous to flow out of the eye.

Both types of surgeries have been proven effective in lowering eye pressure. Some people may still need to use post-surgery eye drop medications to maintain healthy eye pressure.

Surgical Alternatives

Several new surgical options have been developed recently:

  • Express mini-shunt: A small stainless steel device the size of a grain of rice is implanted in the eye to drain the fluid.
  • Trabectome: A device is inserted into the eye through a very small incision at the edge of the cornea. A small portion of the eye's trabecular meshwork, which is responsible for fluid outflow, is removed, which improves drainage. This is usually done as part of cataract surgery.
  • Canaloplasty: An incision is made in the eye and a microcatheter is inserted into the eye drainage system to encourage fluid outflow. This is usually done as part of cataract surgery.
  • Other newer procedures, called MIGS (minimally invasive glaucoma surgeries), are receiving attention from eye surgeons. The currently available iStent is very small and recommended for use at the time of cataract surgery.

You can find more information about these surgical procedures at the Glaucoma Research Foundation.

Additional Information


Topics:
Glaucoma
Medical Updates

Our Readers Want to Know: What Is the Progress of Stem Cell Research for Eye Disease? Answer: It Has a Very Long Way to Go

the ARVO logo

Logo of the Association for
Research in Vision and
Ophthalmology

Of all the eye research developments reported on the VisionAware blog, it is stem cell research for eye disease that generates the most inquiries from readers. Many readers request information about how to join a stem cell clinical trial, or find a doctor who will perform stem cell treatments.

In response to these inquiries, my message is always the same: "Although stem cell research has produced interesting results, it is in its very earliest stages and must be subjected to additional, longer-term, rigorous study and clinical trials, encompassing many more years of research. Success in this area is not a foregone conclusion. At present, stem cell research is fraught with numerous stops and starts, high expectations, and frequent disappointments."

A Small Clinical Trial

The stem cell research that VisionAware has followed most closely involved an 18-patient early-stage clinical trial of human embryonic stem cells (hESC) for the treatment of dry age-related macular degeneration and Stargardt disease.

The research was sponsored by Ocata Therapeutics (formerly Advanced Cell Technology, Inc.) and interim results from these initial surgeries performed in 2011 and 2012 were published in the October 15, 2014 issue of The Lancet, in an article titled Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies.

You can read more about the results of this 18-patient clinical trial at Updated Stem Cell Clinical Trial Results for Stargardt Disease and Dry Macular Degeneration on the VisionAware blog.

Yes, the authors did report encouraging results and gains in vision, but they also emphasized that the purpose of these small early clinical trials was to assess the safety of this new stem cell intervention, stating that "[the cells'] plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumor formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types."

Please note: In February 2016, Ocata Therapeutics was acquired by Astellas Pharma, Inc., a Tokyo, Japan-based pharmaceutical company.

What Is the Status of Stem Cell Research in 2016? An Answer and Update from Investigative Ophthalmology & Visual Science

This stem cell update, focusing on the 18-patient clinical trial, is titled Subretinal Transplantation of Embryonic Stem Cell–Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years and is available as an open-source article in Investigative Ophthalmology & Visual Science, the official journal of the Association for Research in Vision and Ophthalmology (ARVO). ARVO is an international organization that encourages and assists research, training, publication, and dissemination of knowledge in vision and ophthalmology, including low vision.

The authors are Steven D. Schwartz; Gavin Tan; Hamid Hosseini; and Aaron Nagiel, from the Stein Eye Institute, University of California Los Angeles Geffen School of Medicine; and the Singapore Eye Research Institute, Singapore National Eye Center. Dr. Schwartz led the surgical team in 2011 that performed the stem cell treatment of the first two patients in the clinical trial.

First, Some Basic Stem Cell Terminology

Here is a brief explanation of some key terms that are used in many types of stem cell research:

  • Pluripotent: A stem cell that has the power to develop into any type of bodily cell or tissue ("pluri" = many; "potent" = having power)
  • Induced pluripotent stem cells (iPSCs): A type of pluripotent stem cell that can be generated or "reprogrammed" directly from adult cells. Induced pluripotent stem cells require viruses to reprogram the cells, which has the potential to cause cancerous tumors.
  • Embryonic stem cells (ESCs): Can form any cell type in the body. However, they are in limited supply, and – due to their origins – have ethical issues attached to their use.
  • Human pluripotent stem cells (hPSCs): The term includes both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs)
  • Autologous: Involving one individual as both donor and recipient
  • Retinal pigment epithelium (RPE) cells: The deepest cells of the retina. The RPE helps to maintain the health of the retinal photoreceptor cells, called rods and cones. These photoreceptor cells are triggered by light to set off a series of electrical and chemical reactions that helps brain to interpret what the eye sees. The degeneration of the RPE cells also leads to the death of the rods and cones and, ultimately, vision.
  • Immunogenic: Causing, or capable of producing, an immune response.

About the Stem Cell Update and Continuing Research

Edited and excerpted from Subretinal Transplantation of Embryonic Stem Cell–Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years, with the entire report available online:

Safety Issues

Despite the many theoretical advantages of human embryonic stem cells (hESCs) …, there are also [many] safety concerns if the hESC derivatives are to be implanted into humans. The differentiated cell population must be free of pathogens [i.e., bacteria or viruses], possess the characteristics of the differentiated cell, and be free of undifferentiated cells.

… In addition, the cells need to be tested in various pre-clinical models, including immunodeficient animals [i.e., animals with an inability to fight infection], to demonstrate the absence of teratoma formation [i.e., a tumor containing several different types of tissue]; hyperproliferation [i.e., an abnormally high rate of cell reproduction]; or the migration of cells into other [bodily] organs.

Importantly, all studies using the hESC-RPE cells in pre-clinical models showed no evidence of teratoma formation, hyperproliferation, or ectopic tissue formation [i.e., tissue that has migrated into other parts of the body].

Another major consideration in these studies is the possibility that the transplanted cells could initiate an inflammatory response or trigger immunologic rejection. Although cellular rejection itself would be a disappointing outcome, of greater concern is the possibility that an inflammatory reaction in the sub-retinal space could incite further damage to areas of retina that remain functional. Despite cross-species transplantation, preclinical models demonstrated little or no inflammation.

You can read about additional safety, tolerability, and visual improvement outcomes at Study Endpoints: Safety and Tolerability.

Summary and Future Challenges

Pluripotent stem cells have the capacity for unlimited self-renewal and have been proposed as a potential source of therapeutic cells for regenerative medicine. These studies provided the first description of the short- and long-term safety of [hESCs] transplanted into human patients. Given the excellent safety profiles observed thus far, this work sets the foundation for future trials using cellular therapies for regenerative medicine in humans.

Within the confines of these phase 1 trials, the transplanted hESC-RPE cells appear to be well tolerated. None of the 18 patients had an adverse intraocular or systemic event related to the cells. However, a number of patients had adverse events related to the surgery or the immunosuppressive regimen [i.e., drug regimens that suppress the immune, or rejection, response]. So while endpoints such as visual acuity improvements and structural changes seem encouraging, enthusiasm must be tempered.

Initial safety studies such as this one are typically limited by the lack of a masked control group, the advanced disease present at baseline, and the small number of patients. Visual acuity measurements can be unreliable in patients with advanced geographic atrophy.

A second major challenge is the use of solid organ transplant-dose immunosuppressive regimens. Subsequent studies will attempt to reduce the amount of immunosuppression and test whether it is even necessary to any degree.

As always, the burden of proof rests on upcoming randomized, multicenter trials. With more sophisticated multimodal imaging and functional testing such as adaptive optics-based scanning laser ophthalmoscopy and microperimetry, it may be finally possible to determine whether the transplanted cells are having a direct effect on visual function at particular sites in the retina.

Thus, this small 18-patient phase 1 clinical trial represents the beginning of a many-years-long series of trials and refinements. There are many questions that must be answered if the research is able to proceed to larger-scale clinical trials. To repeat: Success in this area is not a foregone conclusion.

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.

VisionAware will provide updates on this stem cell research if and when they become available.

Additional Information


Topics:
Clinical Trials
In the News
Low Vision
Macular Degeneration
Medical Updates
Stargardt Disease

Follow Us:

Blog Archive Browse Archive

Join Our Mission

Help us expand our resources for people with vision loss.