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New Research: Combat-Related Blast Exposure Can Result in Prolonged Retinal Injury, Even in the Absence of Detectable Brain Changes

According to VisionAware's Gregory L. Goodrich, Ph.D., writing about combat-related traumatic brain injury (TBI) and its effect on vision:

"... It can be argued that … it took the wars in Afghanistan and Iraq to highlight the fact that head injury often leads to visual loss and/or visual dysfunctions. These wars have resulted in over 253,000 traumatic brain injuries (TBI). How many of these TBIs resulted in vision loss or dysfunction is not known."

"Kevin Fricke has estimated that between the years 2000 and 2011, over 54,000 U.S. troops experienced an eye injury or visual loss/dysfunction. He estimated the direct medical cost for these troops to be $2.82 billion dollars. The projected cost to the economy over the lifetime of these individuals, including rehabilitation, lost wages, and other costs is estimated to be an additional $24.286 billion."

Source: K. Fricke (2012). Costs of Military Eye Injury, Vision Impairment, and Related Blindness and Vision Dysfunction Associated with Traumatic Brain Injury (TBI) without Eye Injury. Report prepared for the National Alliance for Eye and Vision Research.

photo of Jeffrey Mittman

Master Sgt. Jeffrey Mittman,
wounded by a roadside bomb
in Baghdad, Iraq

Most recently, a research group from Iowa State University and the National Animal Disease Center, United States Department of Agriculture has built upon this prior research, reporting that combat-related blast exposure which does not cause detectable changes in the brain can result in long-term retinal injury.

Co-author M. Heather West Greenlee, Ph.D. states that "In this model, the retina may serve as an area of the central nervous system that is more vulnerable than the brain and, therefore, may be an effective and more sensitive indicator of low-level injury due to blast-wave pressure. We believe that eventually examination of the retina may help to assess the magnitude of exposure and identify individuals who may need or benefit from proactive treatments as they become available."

From the American Journal of Pathology

This new traumatic brain injury and retinal injury research, titled Lasting Retinal Injury in a Mouse Model of Blast-Induced Trauma, has been published in the July 2017 edition of the American Journal of Pathology, the official journal of the American Society for Investigative Pathology.

The authors are Najiba Mammadova, Shivani Ghaisas, Gary Zenitsky, Donald S. Sakaguchi, Anumantha G. Kanthasamy, Justin J. Greenlee, and M. Heather West Greenlee, from Iowa State University and the National Animal Disease Center, US Department of Agriculture, Agricultural Research Service, Ames, Iowa.

About the Research

Excerpted from Retina may be sensitive gauge of blast-wave pressure injury, via Medical Xpress:

There is a lack of validated biomarkers, as well as limited understanding of the underlying mechanisms of retinal injury due to blast exposure.

[Editor's note: A biomarker is 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.

Currently, diagnosis and measurement of progression of disease rely upon clinical observation, and despite a "normal" [eye] examination, some patients present with chronic visual complaints. Combat veterans show a high percentage of visual field defects, light sensitivity (photophobia), eye movement problems, and decreased contrast sensitivity.

"Our results may explain symptoms of visual dysfunction reported by combat veterans who have experienced traumatic brain injury," explained lead investigator Heather West Greenlee, PhD. "These results are not surprising, since the retina is the most accessible part of the central nervous system; as such, it is particularly vulnerable to injuries similar to those that affect the brain."

Investigators used a compressed air-driven shock tube system to expose mice to blast wave pressure of 300 kPa (equivalent to three times atmospheric pressure) per day for three days. After 30 days, the mice were subjected to a variety of tests to probe for cognition or motor function deficits and subsequently underwent analyses of the retina and brain.

Retinas of blast-pressure-exposed animals displayed several pathological changes, including activation of [retinal glial cells], microglial activation, inflammation, and photoreceptor cell death. Eyes on the same side as the blast showed greater abnormalities than eyes on the other side. Interestingly, researchers also found accumulation of tau, the protein associated with pathologies of the central nervous system including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy [i.e., inflammation of the brain or abnormal brain function].

[Editor's note: Glial cells surround neurons, or nerve cells, and provide support for, and insulation between, them. Microglia are a type of glial cell located throughout the brain and spinal cord. They act as the primary form of immune defense in the central nervous system.]

These findings showed the prolonged impact of blast injury on the retina, as well as the vulnerability of particular retinal cell types to blast injury. Despite the effects in the retina, there were no detectable cognitive or motor deficits and no evidence of injury in the striatum or pre-frontal cortex, areas of the brain responsible for motor function. Executive decision making and memory remained unaffected.

More about the Retina and Its Function

The retina is the light-sensitive tissue that lines the inside surface of the eye, much like wallpaper. The macula is the small sensitive area in the center of the retina that provides clear central vision. The fovea is located in the center of the macula and provides the sharpest detail vision.

The retina contains photoreceptor cells that convert (or process) incoming light into electrical impulses. These electrical impulses are carried by the optic nerve (which resembles your television cable) to the brain, which finally interprets them as visual images.

There are two types of photoreceptors: rods and cones, which are the light-processing cells responsible for peripheral (side) and central (straight-ahead) vision.

Rods

  • The specialized, highly light-sensitive retinal processing cells that are able to function in low light levels. They provide peripheral (or side) vision, are responsible for dark adaptation, and are most sensitive to movement/motion. They are less sensitive to color perception.
  • A normal retina contains approximately 120-150 million rods, primarily in the peripheral, or outer, retina.
  • Rods provide scotopic vision which refers to eyesight in low light conditions.

Cones

  • The specialized retinal processing cells that function in bright light levels and provide central (or straight-ahead) vision, along with sharp visual acuity, detail, and color vision. They require bright light to function and are not sensitive to lower light levels.
  • A normal retina contains approximately 6-7 million cones, primarily in the macula, the small area in the center of the retina that provides clear central vision. Cones are the most concentrated in the fovea, which is located in the center of the macula and provides the sharpest detail vision.
  • Cones provide photopic vision, which refers to eyesight in daylight conditions.

More About the Study from the American Journal of Pathology

Excerpted from the study Abstract:

Traumatic brain injury due to blast exposure is currently the most prevalent of war injuries. Although secondary ocular blast injuries due to flying debris are more common, primary ocular blast exposure resulting from blast wave pressure has been reported among survivors of explosions, but with limited understanding of the resulting retinal pathologies.

Using a compressed air-driven shock tube system, adult male and female C57BL/6 mice [i.e., a common inbred strain of laboratory mice] were exposed to blast wave pressure of 300 kPa (43.5 psi) per day for 3 successive days, and euthanized 30 days after injury…. Primary blast wave pressure resulted in activation of Müller glia, loss of photoreceptor cells, and an increase in phosphorylated tau in retinal neurons and glia.

We found that 300-kPa blasts yielded no detectable cognitive or motor deficits, and no neurochemical or biochemical evidence of injury in the striatum or prefrontal cortex, respectively. These changes were detected 30 days after blast exposure, suggesting the possibility of long-lasting retinal injury and neuronal inflammation after primary blast exposure.

VisionAware will continue report on this research as results become available.

Additional Information About Traumatic Brain Injury from VisionAware


Topics:
Health
Low Vision
Stroke or Brain Trauma
Veterans

Taking It to the Streets: Make the 21st Century Agenda on Aging and Vision Loss Happen on a Local Level

As highlighted in a post in May regarding critical issues for older persons with vision loss, AFB has joined with other advocates in a renewed 21st Century Agenda on Aging and Vision Loss. Why is this important? Check out the facts.

man holding white cane speaking at protest   

Building the Case

As laid out in the www.afb.org/aging, the Agenda's web page, older adults with vision loss are frequently overlooked and underserved. Vision loss can also exacerbate normal changes associated with aging..

Loneliness, Isolation, and Vision Loss

Colleen O'Donnell, OT, CVLT, notes that among older persons, visual impairment is associated with depressive symptoms and lower life satisfaction. This may be due, in part, to activity limitations and decreased self-esteem (both factors connected to isolation), according to Brown & Barrett. Additionally, the Centers for Disease Control studies indicate that older adults with moderate or extreme vision loss are more likely to experience heart disease and diabetes and are less likely to report excellent or very good health than seniors without vision loss (2011).

Both aging and vision loss can each lead to isolation; thus, isolation and its negative impacts on health and quality of life major concerns of older adults with vision loss and their families. One older person wrote to the American Foundation for the Blind (AFB), "Since my vision went south… the few resources available assume that all I will ever do is go to doctor appointments. …I would like to have a social life, but all hope of that is fading fast."

Even more disheartening is a study by Berger of 26 older adults with vision loss, that found that, despite desiring and enjoying being active in their communities, all of her participants had difficulties engaging in leisure activities outside their homes. These seniors cited "challenging environments, struggling to get there, feeling vulnerable, having decreased energy, and lacking assertiveness" as barriers to participation (pp. 9-10).

Agenda Seeks to Tackle These Issues with Four Goals

  • Goal One: Funding for services
  • Goal Two: Ensuring availability and quality of professional services
  • Goal Three: Collaboration across service delivery systems to maximize resources for tackling critical needs (e.g. transportation)
  • Goal Four: Funding for low vision devices

Progress on Each Goal

Goal One

A fact sheet (links to a Word file) on the numbers of older people with vision loss in this country and the need for services has been developed for use in educational and advocacy efforts.

Goal Two

Goal participants are working on surveys to determine the "state of the nation" regarding qualified personnel. Once these surveys are completed, the group will work on next steps.

Goal Three

This goal group has chosen to concentrate on transportation and is currently ramping up its efforts in this area.

Goal Four

Legislation has been introduced in Congress (H.R. 2050) that provides for a Medicare demonstration project to evaluate the fiscal impact of covering low vision devices as durable medical equipment under Part B of the Medicare program, and will work toward the passage of this important legislation for all people with low vision, especially seniors. The American Council of the Blind is leading this effort.

What Can You Do in Your Own Community?

Get involved in advocacy efforts related to the welfare of older persons with vision loss. Health care is a major issue and the Senate is trying to schedule a vote the week of the 26th to repeal significant parts of the Affordable Care Act that would affect Medicaid.

Action Steps

Call your Senators and tell them, No Cuts or Caps to Medicaid!. You can call your Senators by dialing the Capitol Switchboard at (202) 224-3121. When calling, here are some talking points:

  • Medicaid is the largest single payer of long-term care in our nation.
  • Medicaid is the only way most people can afford long-term care.
  • Medicaid allows long-term care consumers to stay in their homes.
  • For nursing home residents and other long-term care consumers, cuts or caps to Medicaid would result in cuts to available care and services and would make it harder to qualify for care.

Get Involved in the 2lst Century National Agenda on Aging and Vision Loss

It may be national in scope, but change starts at the grassroots level. How does your community measure up?

Talk to senior centers and other locations that provide services and programming for older persons about what they can do to be inclusive.

Heed Amy Bovaird's advice on "building bridges" in her post on the value of senior centers. She says, "If there aren’t currently accommodations, let’s speak up and tell senior centers what’s needed to enable us to better fit in to the centers. Whether it’s something physical like more lighting, audio description services, activities in braille or large print, human guides, open discussions of emotional needs such as through support groups, transportation—whatever the case may be, let’s bring that information to the table and continue to change our communities for seniors who are visually impaired."

Keep up with what is going on with the Agenda. To find out more about Agenda activities including goal group initiatives, join our Google Group listserv and select "contact the owner," or e-mail Sarah Malaier.

Additional Information

Medicare Coverage of Low Vision Devices Act Needs Advocacy and Support

Understanding Our Shifting Health Insurance Landscape


Topics:
Aging
Public Policy

Aira: A New and Exciting Access Service for People Who Are Blind or Visually Impaired

Aira logo showing eye and word Aira

Aira (pronounced "EYE-rah") has made quite a debut on the access technology scene recently. It has impressed the likes of CSUN2017, Assistive Media, Inc., and won "Best in Show" honors at the Mobile World Congress in Barcelona. I learned about Aira at this year’s American Foundation for the Blind Leadership Conference, and it wowed me too!

woman using guide dog walking across street and wearing aira glasses  

What Is Aira?

Aira calls itself a "visual interpreter for the blind," enabling users to explore the world in augmented ways using an eclectic and robust collection of technologies and services. It combines wearable smart glasses with an embedded video camera paired with a smartphone, a portable WiFi hotspot, and a network of live certified agents who assist the user remotely in real-time. The trained agents see the world through the smart glass worn by the customer and describe the view. They respond to requests for information from the user, working at a specially-designed dashboard that efficiently connects to information via the video camera, GPS, and other sources of data. The result is an augmented reality experience in which users can access helpful information in a friendly, efficient manner to improve their mobility and independence.

aira agent looking a computer with view of what aira user is seeing in street crossing

How Can Aira Help?

Paul Schroeder, an Aira team member, states, "It is more than a navigation tool; it is an ‘information service’ at its heart." Customers may use Aira to travel independently while learning about their surroundings. The agent can give detailed descriptions of buildings, landscapes, and people in the environment. If a customer wants to know more about the restaurant he/she is headed to for lunch, the agent can quickly access a Yelp review. Aira agents can read print like menus, business cards, signs and handwritten notes through the smart glass video camera. They can even take photos for the user and e-mail them. Aira can help with tasks like shopping, homework, or to learn a new skill like origami. Erich Manser, who is legally blind from retinitis pigmentosa, recently ran the Boston marathon assisted by Aira. The possibilities are endless, and customers are discovering innovative ways to apply the Aira service daily.

What Does Aira Cost?

Currently, customers pay a monthly subscription for the service plan of their choice, and there is no contract or other fees. All plans include:

  • Lightweight, stylish smart glasses
  • Data (via AT&T Mifi)
  • Roll over of unused minutes
  • Insurance for hardware
  • Training Session
  • 7 a.m. - 7 p.m., Seven days a week access to agents

Four Plans Available

Each plan comes with bonus minutes for a three-month trial period. The service can be changed or canceled at any time.

  1. BASIC $89 - 200 Three-Month Intro Minutes/ 100 Regular Minutes
  2. PLUS $129 - 400 Three-Month Intro Minutes/200 Regular Minutes
  3. PRO $199 - Unlimited Three-Month Intro Minutes/ 400 Regular Minutes
  4. PREMIUM $329 - Unlimited Three-Month Intro Minutes/ Unlimited Regular Minutes

More About the Agents

Live agents are the cornerstone of Aira, and they are internally trained and vetted. Through extensive interactions with the blind community and blindness professionals like Orientation and Mobility instructors and Vision Rehabilitation Therapists, they learn what customers need and want. The service is personalized as agents learn preferences and create a profile on each user. Agents are trained in the terminology and etiquette of blindness to communicate effectively with users. They multi-task, read maps, and articulate information clearly.

It is a challenging job that requires managing a complex platform and busy screen while the customer asks questions. At the same time, agents are doing Internet searches and delivering detailed information. It is important to note that Aira agents do not provide opinions nor make decisions on safety issues; they are never to be substituted for a customer’s own travel skills and judgement. In fact, Mr. Schroeder remarked "the better travel skills you have, the better you will be able to use Aira."

Aira Now Hiring

Aira is looking for exceptional people who are interested in becoming a part of this exciting team. They are now hiring agents, engineers, and more. They offer competitive compensation and benefits packages as well as an opportunity to make a meaningful impact on others’ lives.

How Aira Plans to Expand

Aira continues to evolve and improve its platform, services, and equipment. It is currently working on developing its own version of smart glasses with integrated video, audio, and WiFi for a more streamlined design. Artificial intelligence will play a larger role in services as the product is scaled though it will not replace live agents. There is discussion about hiring agents with specialized skills and expertise to assist users with unique tasks, and Aira will continuously add existing technologies and services like Uber, which has joined the cadre.

aira user looking at overhead restaurant menu using glasses

Important Partnerships

AT&T manages the live streaming data and video feed the agents receive on their dashboards. It has given this data stream priority to decrease hiccups and delays ensuring efficient operation of the service. The National Federation of the Blind and the American Foundation for the Blind have been staunch supporters throughout the development of Aira. Kirk Adams, CEO of the American Foundation for the Blind says:

"Whether the task at hand requires operating a sophisticated console or safely navigating a sprawling airport, it's clear that Aira's new technology represents a quantum leap in independence and accessibility for those with visual impairments."

He believes Aira can "widen opportunities for employment, education, and enhanced quality of life."

What Do Users Think?

First users of Aira say it "redefines freedom" and "it gives them information about things they never knew existed." Eric Duffy wrote in the April 2017 issue of the Braille Monitor:

"Aira provides sight assistance only when you request it. It is available when you need it, and there is no waiting until later when it is more convenient for someone to provide the visual information you have requested. Aira has not made me more dependent on sight; rather, it has changed the way I do some things. As far as I am concerned, this is a change for the better."

What Do You Think?

Aira has the potential to make you more efficient and confident as a person with blindness. How do you imagine using this cutting-edge technology in your daily life? How could Aira enrich your experiences? Visit the Aira website to learn more and to check out a video demonstration of Aira. Follow Aira on Facebook for its latest news, and check out Aira on YouTube.


Topics:
Assistive Technology
Getting Around
Low Vision
Orientation and Mobility
Reading
Technology

New Research: A Potential Eye Drop Treatment Could Take the Place of Injectable Drugs for Wet Macular Degeneration

the ARVO logo

Logo of the Association for
Research in Vision &
Ophthalmology

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").

From a patient's point of view, however, the "gold standard" for treatment would be a self-administered eye drop that replicates the function of these injectable drugs. Unfortunately, past eye drop research has proven to be unsuccessful or inconclusive:

  • Squalamine eye drops, in combination with Lucentis injections, produced disappointing clinical trial results and failed to reduce the average number of Lucentis injections required by the clinical trial participants.
  • Application of an eye drop compound called PPADS has not progressed from the initial "proof of concept" results reported in 2014.

This month, however, a research team from the United Kingdom reports the development of yet another novel method for delivering Lucentis and Avastin as an eye drop instead of an injectable drug, using cell-penetrating peptides (explained below). Please note that this "proof of concept" research is in its earliest stages and has been conducted only with cultured human eye cells, and rat, pig, and mouse models. It has not yet advanced into human trials. The concept of a possible topical/eye drop treatment may yet show promise for persons with wet macular degeneration.

From Investigative Ophthalmology & Visual Science

This new eye drop/macular degeneration research, titled Topical Delivery of Anti-VEGF Drugs to the Ocular Posterior Segment Using Cell-Penetrating Peptides (explained below), has been published as an open-source article in the May 2017 issue of 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 Felicity de Cogan; Lisa J. Hill; Aisling Lynch; Peter J. Morgan-Warren; Judith Lechner; Matthew R. Berwick; Anna F. A. Peacock; Mei Chen; Robert A. H. Scott; Heping Xu; and Ann Logan, from the University of Birmingham, United Kingdom; Queen's University Belfast, United Kingdom; and Moorfields Eye Hospital Dubai, United Arab Emirates.

First, Some Terminology Used in the Research

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

  • Posterior segment of the eyeball: The back 2/3 of the eye that includes the vitreous, retina, choroid, and optic nerve.
  • Cell-penetrating peptides (CPPs): Peptides are fundamental components of cells that carry out important biological functions, including regulating the activities of other molecules. Cell-penetrating peptides (CPPs) are peptides that are able to cross, or penetrate, cell membranes and gain access to the interior of almost any cell. Because of this characteristic, CPPs are considered promising candidates for the transport of drugs or other therapeutic substances to the interior of cells, including the cells in the eye and retina.
  • 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.
  • Vector: A "carrier" molecule that transports drugs or therapeutic substances into another cell, where they can be expressed.
  • 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).
  • 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.
  • VEGF: A protein, called vascular endothelial growth factor, that stimulates abnormal blood vessel growth in the retina and macula.

About the Research

Excerpted from Scientists Develop eye Drops to Treat Age-Related Blindness, via Medical Xpress:

Scientists at the University of Birmingham have developed a type of eye drop which could potentially revolutionize the treatment of one of the leading causes of blindness. The results of the collaborative research could spell the end of painful injections directly into the eye to treat the increasingly common eye disorder known age-related macular degeneration (AMD).

AMD is currently treated by repeated injections into the eye on a monthly basis over at least three years. This is a problem because, apart from being an unpleasant procedure for patients to undergo, the injections can cause tearing and infections inside the eye and an increased risk of blindness.

Now scientists led by [co-author] Dr. Felicity de Cogan, from the University of Birmingham's Institute of Inflammation and Aging, have invented a method of delivering the injected drug as an eye drop instead, and their laboratory research has obtained the same outcomes as the injected drug.

The drop uses a cell-penetrating peptide (CPP) to deliver the drug to the relevant part of the eye within minutes. Dr. de Cogan said, "The CPP-drug has the potential to have a significant impact on the treatment of AMD by revolutionizing drug-delivery options. Efficacious self-administered drug application by eye drop would lead to a significant reduction in adverse outcomes and health care costs compared with current treatments. The CPP-plus drug complex also has potential application to other chronic ocular diseases that require drug delivery to the posterior chamber of the eye."

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.

More About the Study from Investigative Ophthalmology & Visual Science

Excerpted from the study Introduction, Discussion, and Conclusions, with the full article available online:

The aim of this study was to assess the potential for cell-penetrating peptides (CPPs) as "chaperones" within a topical ocular drug-delivery platform for the passage of therapeutic titers [i.e., the therapeutic concentration of a solution] of VEGF antagonists [i.e., inhibitors] to the posterior segment of the eye. Use of novel CPPs as ocular drug-delivery agents would facilitate clinical administration of large biopharmaceuticals, such as ranibizumab [i.e., Lucentis] or bevacizumab [i.e., Avastin], in the form of an eye drop.

The development of this eye drop delivery platform will have wide-reaching implications for improved patient care, by reducing the side effects and treatment costs associated with both current clinically effective drugs and novel candidate drugs.

Here, we have evaluated CPP-mediated eye drop delivery of anti-VEGF antibodies in rodent and porcine [i.e., pig] models to determine dose delivery and pharmacokinetics [i.e., the movement of drugs through the body]. We also have used an established "in vivo" rodent model of choroidal neovascularization (CNV) to compare the efficacy of anti-VEGF drugs when delivered topically with CPPs or by intravitreal injection.

Anti-VEGF agents are a well-established treatment for [wet AMD]; however, the side effects from delivery by intravitreal injection represent a significant problem. Accordingly, this study investigated the use of CPP as a novel topical delivery vehicle for anti-VEGF agents to the posterior segment, negating the need for invasive intravitreal injections.

This study demonstrates that CPP can successfully deliver topically applied [i.e., eye drop] anti-VEGF drugs into mouse, rat, and pig eyes, and showed bioactivity of the topically delivered drug in a relevant disease model that was equivalent to other AMD drug-delivery methods.

Specifically, we have shown that CPPs have high penetrating capabilities for biological barriers in the eye with low toxicity and can deliver clinically relevant concentrations of anti-VEGF drugs, such as ranibizumab [i.e., Lucentis] or bevacizumab [i.e., Avastin], to the posterior segment of the eye.

In particular, these CPPs have the capacity to noninvasively deliver therapeutics … to anterior and posterior ocular segments to give outcomes comparable to … injected drugs.

If the results were translated to human eyes, it would allow the topical delivery of a wide range of ocular drugs that currently can be delivered only by intravitreal or subconjunctival injections. This would reduce treatment costs, time in clinic, and harmful side effects, while allowing patient self-administration, so that new drug-delivery regimens can be better tolerated.

VisionAware will continue report on this macular degeneration research as results become available.

Additional Information About Macular Degeneration


Topics:
In the News
Low Vision
Macular Degeneration
Medical Updates

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

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