From the UIC Science Blog
Can reducing the buildup of a protein associated with Alzheimer’s disease in the eye help treat macular degeneration?
Sharon Parmet
September 2014
David Pepperberg, professor of ophthalmology in the UIC College of Medicine, together with Louis Hersh, professor of molecular and cellular biochemistry at the University of Kentucky, have received a two-year, $120,000 grant from the BrightFocus Foundation to develop and test a new approach to the treatment of macular degeneration.
The disease is a leading cause of vision loss in older individuals and has been estimated to affect approximately 15 million Americans. It causes damage to the light-sensitive photoreceptor cells of the macula, a small spot near the center of the retina and the part of the eye needed for sharp, central vision, which lets us see objects that are straight ahead.
What causes macular degeneration?
Macular degeneration is not a disease that has a single cause – it is multi-factorial. It can progress to different extents, and has genetic associations. There are also environmental factors that have been linked to macular degeneration, including smoking. Heavy smokers have a decidedly increased risk of developing macular degeneration in their lifetimes. There is also some research that suggests that amyloid-beta, a neurotoxic protein that has been implicated as one of the main drivers of Alzheimer’s disease, may also play a role in macular degeneration.
What are the symptoms of macular degeneration?
Imagine if in the center of your field of vision, there were a sort of gray smudge covering the area that you’re looking at, and you can’t move your eye away, because the smudge moves too. This is an oversimplified way of describing the experience of people with macular degeneration. It’s so devastating because the center of your field of vision is what you use for facial recognition, driving and reading.
There are two forms of macular degeneration – dry and wet. Dry is the most common and occurs when the light-sensitive cells in the retina die. The wet form is more severe, and it includes the abnormal growth of tiny blood vessels in the back of the eye that leak blood and fluid into the eye which further diminishes visual perception. The wet form develops from the dry form.
Can you describe the research that the BrightFocus Foundation grant will help support?
My research, which is in collaboration with Louis Hersh at the University of Kentucky, focuses on a molecule called amyloid-beta. There is a huge amount of literature addressing the roles of amyloid-beta in the development in brain degenerative disease like Alzheimer’s. There is a much smaller, but increasing literature and research effort in vision that is testing the possibility that amyloid-beta also may also have a role in the development of degenerative retinal disease like macular degeneration.
The thinking is that an excess buildup of amyloid-beta, due to either an abnormal overproduction or deficient clearance of it, is damaging in one or more respects to the neural tissue that makes up the retina.
We are developing technology that can hopefully reduce the excessive buildup of amyloid-beta in the eye tissues by introducing a type of enzyme that degrades amyloid-beta. We are investigating two ways to deliver the enzyme to the retinal tissue in mice.
The first is through intravitreous injection. The vitreous is the large fluid compartment that fills the globe of the eye and maintains its structure and serves multiple purposes. Intravitreous injection of drugs for eye disease is a widely used technique in ophthalmology.
We will look at different amounts and frequencies of injection of a fluid containing the enzyme and analyze the effects on amyloid-beta in the retina at defined times after treatment and assess changes in vision in the mice.
The second delivery mechanism introduces the enzyme to the eye using a gene therapy approach. A viral particle that has been rendered nontoxic is used to encapsulate the gene that makes the enzyme, and the viral particles that contain the gene are added to a small volume of fluid that is then intravitreously injected into the eye. The idea is that the virus reaches its target cells and delivers the gene, allowing the cell to express the enzyme itself.
The retina is our target, but right now, we don’t yet know to what extent it will be important to target a particular class of cells in the retina versus having a more general targeting. That’s one of the things we will be looking at.
Ideally, the gene therapy would be a one-time only procedure, but that remains to be seen. It’s not guaranteed that a single treatment will last forever because of cell turnover and other issues, but the concept is that you introduce the gene and it resides in its target cells from that time forward making its gene product, which is, in our case, the enzyme that degrades amyloid-beta.
Is the enzyme harmless?
The enzyme exists in many tissues throughout the body, including the eye. Much of our work, in addition to testing efficacy of delivery of the enzyme, is to determine if there are unwanted side effects that may be potentially damaging. We’re just at the beginning.
What are some other approaches to treating AMD?
Research groups around the world are pursuing multiple approaches that are aimed at repairing vision lost in AMD. These approaches range from pharmacological treatments, to stem cells that can promote new retinal cell growth, to electronic implants that can stimulate the retina when light is incident on the electronic device. An approach that my colleagues and I are investigating is to develop light-sensitive molecular structures that can be interfaced with non-photoreceptor retinal cells that often remain healthy in AMD. These “downstream” retinal cells are not ordinarily light-sensitive. However, if they can be made light-sensitive by the attachment of the specialized molecules we are developing, it may be possible to initiate visual signals in these cells and thus bypass the vision loss problem caused by deterioration of the retina’s photoreceptors.
Link to posting on UIC Science: http://uicscience.tumblr.com/post/97730255958/q-a-with-retina-expert-david-pepperberg-can