Aberrant Blood Vessel Growth in AMD: A New Animal Model

Sarah McFarlane, PhD
University of Calgary (Canada)
Year Awarded:
2017
Grant Duration:
July 1, 2017 to March 30, 2020
Disease:
Macular Degeneration
Award Amount:
$123,160
Grant Reference ID:
M2017002
Award Type:
Standard
Award Region:
International
Sarah McFarlane, PhD

Molecular Regulation of Choroid Neovascularization

Summary

In neovascular age-related macular degeneration (AMD), the sprouting of new blood vessels (angiogenesis/neovascularization) leads to the death of the nerve cells of the retina. Neovascular AMD places a substantial burden on patients and the healthcare system. Current approaches to block new blood vessels from forming are not effective in many patients and they have serious side effects. There’s an urgent need for effective new ways to prevent these faulty new blood vessels from forming, but not affect the health of retinal nerve cells or the normal blood vessels. To address this need, we are developing a genetic animal model where we can rapidly identify novel, safe and effective drugs for the treatment of neovascular AMD. 

Details

Imagine how difficult it is for a patient and their family and friends when they lose vision, as is the case in a disorder such as age-related macular degeneration (AMD), where the unexpected sprouting of weak and leaky new blood vessels leads to death the ath of the nerve cells of the retina. Current approaches to block new blood vessels from forming are not effective in many patients and they have serious side-effects, and new therapies are needed. Our overarching goal is to investigate a mechanism that we think ensures just the right amount of blood vessel growth around the eye as it first forms in the embryo, with the hope that it can be reintroduced into the adult AMD eye to block the growth of the faulty and dangerous blood vessels. To do this we need to understand how this mechanism works normally, so we will test this therapeutic approach using an animal model where the pathway regulating normal retinal blood vessel growth has been removed genetically. We can then ask whether blood vessels overgrow in the absence of this regulatory pathway; whether overgrowth causes fluid loss from the vessels that in turn causes eye cells to die; and how the eye might try to recover even without any other intervention. Once we know how this pathway works, and what happens to eye cells when it isn't around, we will conduct some safety experiments to make sure that the therapy we’ve devised to replace this cell growth pathway, when active in an adult eye, won't harm eye cells. To do that we will activate the pathway in adults of this zebrafish model using gene manipulation techniques, then test the health of eye cells. Then we will be ready to start testing this new therapeutic approach in an experimental animal model where we have induced pathological blood vessel growth, in order to figure out the exact experimental parameters where we can best mimic the kind of vessel growth we see in AMD. By the end of the two years, we will have worked out how good this experimental approach is at preventing blood vessel growth, and also any possible side effects on healthy eye cells. If everything looks good, we will have a model of pathological blood vessel growth in hand, and we can get down to the business of seeing whether the proposed therapy helps shut down bad blood vessel growth and protects eye cells.

About the Researcher

I have worked the last 25 years trying to understand how eye cells are made, connect to one another, and stay healthy as we age. I grew up outside Montreal and did my BSc (1987) and PhD (1992) at McGill University. Here I developed an interest in the nervous system and how neural circuits are formed. I was lucky to join the lab of Dr. Christine Holt at the University of California, San Diego in 1993, to continue my research training, trying to understand at a single cell level how the retinal cells of the eye connect with brain. This was a wonderful time of learning and experimenting that set me up to take a job as an assistant professor at the University of Calgary, Alberta, Canada, in 1993. I have been here since, working with an excellent cadre of vision biologists and developmental biologists. I have been a full professor in the Department of Cell Biology and Anatomy since 2007, and continue to work actively in the lab and take a particular interest in graduate education. My lab is currently moving our interest in retinal circuit formation in a new and related direction: how these circuits need to be protected over time to ensure proper visual function. In particular, we are asking how molecules that are important in eye development both prevent and protect against damage in disease states such as AMD and encourage regeneration of cells and their nerve fibers after injury.

Personal Story

For more than 25 years, I have been privileged to work in the world of basic science, where scientists try to identify the fundamental mechanisms that drive a biological process. I really enjoy figuring out how things work, and getting trainees interested in the natural and biological world around them, and I still get excited as I sit at the microscope or look at data. I firmly believe that basic knowledge is absolutely necessary; if we are going to be able to repair injured retinas, we need to know how different retinal cells are made normally, so we can remake them in a culture dish and use them to replace injured retinal cells. Similarly, we need to know how these cells are nourished by the blood vessels, yet manage to discourage excess and pathological blood vessel growth. And finally, a huge goal is to discover protein signals that we could reactivate in a diseased or injured eye, signals that act early to make naive cells multiply in sufficient numbers to make an entire eye.

These research priorities that will lead to the development of new therapies became particularly striking when I was diagnosed five years ago with glaucoma--a degenerative disorder where the retinal nerve cells that carry visual information to the brain slowly die. I understand the importance of getting the research right so that we reveal the building blocks to fix or slow vision loss in patients. I am one of those patients, and I want to be able to continue to enjoy hiking with my scientist husband, watch the soccer games of my two boys, and try to grow tomatoes in a beautiful, but way too short Calgary summer. My lab is very appreciative of and excited to use the funds provided by the Brightfocus Foundation to try and understand how retinal health is normally regulated and to test whether reactivation of these proteins could help people with wet AMD. 

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