About Eye Disease
There are a number of diseases and conditions that cause visual impairment or blindness. There are diseases that affect the cornea and the retina, as well as injuries to the surface of the eye and the optic nerve. All of these conditions are promising targets for stem cell treatment.
Some eye diseases can be traced to a genetic defect, such as Stargardt’s disease and retinitis pigmentosa (RP). Others begin because of another illness, such as diabetic retinopathy, not an uncommon complication of diabetes. The most common eye diseases are associated with aging, most notably cataracts, glaucoma and age-related macular degeneration (AMD).
Causes, Symptoms and Treatment
In many of these conditions, early diagnosis is critical to prevent permanent and irreversible damage, since drug treatment or surgery is available. In other conditions, the prognosis is poor.
Age-related macular degeneration
AMD is a retinal degenerative disease associated with defects in the retinal pigment epithelial cells or in the photoreceptors themselves, which are responsible for supporting vision in the retina. The failure of these cells (especially the cones in the center or macula of the retina) leads to progressive loss of central vision and sometimes scarring in the back of the eye. New blood vessels can start to grow in the retina and then leak fluid. This advanced, rarer form is known as “wet” as opposed to “dry” AMD, and accounts for 10 per cent of cases.
Dry AMD, which accounts for 90% of cases, while usually considered not as dramatic, presents the spectre of progressive disability for millions of people resulting ultimately in blindness. It is now the leading cause of blindness in people over 60, and there is no treatment. About 25 per cent of this population has some degree of visual loss due to AMD, a figure that is expected to triple within the next 10-20 years. There is an urgent need for prevention and treatment strategies for age-related macular degeneration.
The cornea can also be injured or damaged due to disease. One of the most common indications for corneal transplant is blindness caused by infection with herpes simplex virus. With approximately 500,000 new cases per year in the US, it is a major concern, since transplantation depends on the availability of replacement corneas. Corneal transplants, which number about 40,000 per year in the US, have traditionally relied on retrieving a healthy cornea from a cadaver.
What can stem cells do?
The cornea
These statistics convey the urgency for scientists to find new ways to generate healthy corneal tissue – for either intrinsic repair (repairing the damaged cornea from within) or extrinsic repair (transplanting a new cornea created in the lab).
Advances are coming quickly in this field, with evidence that human embryonic stem cells can generate new corneal tissue, which can then be grafted into place. Intrinsic repair, however, requires better understanding of the cell signals that would differentiate the stem cells within the eye to replace the cells that have been damaged by disease.
There are several different kinds of stem cells in the eye, each of which serve a different function. Limbal stem cells (sometimes called corneal stem cells) support the cornea and protect the eye from wear and tear by refreshing the cells on the surface of the eye. The conjunctiva, which covers the surface of the eye, is a thin layer of tissue that nourishes and lubricates the eyes. Conjunctival stem cells play a role in continually bathing the eye in tears and mucous. Both limbal and conjunctival stem cells can be grafted onto existing tissue to repair damage.
However, what about the ability to see?
The Retina
The retina is the part of the eye that receives light and discerns images, words on a page, faces. Retinal stem cells, the cells responsible for generating all of the retinal cells that are necessary for sight, are found in the thin black ring around the coloured iris, and they are among the easiest human cells to grow in a laboratory. These adult retinal stem cells are the source of photoreceptors, known as rods and cones, and of the cells that support them, known as retinal pigment epithelial cells. Once retinal stem cells have created their differentiated progeny during fetal development, retinal stem cells apparently become dormant. Therefore, unlike the blood and some organs, the retinal stem cells responsible for sight do not regenerate differentiated retinal cell types like photoreceptors in the adult. Thus, any damage had long been considered irreversible.
The discovery of stem cells in the retina by Dr Derek van der Kooy in Canada in 2000, and the subsequent progress in generating them from human embryonic stem cells, has led to realistic hopes that blindness and vision impairment from degenerative eye diseases can be reversed using stem cell therapy.
Future Directions
The London Project is a team launched in 2007 in the UK dedicated to beginning clinical trials using stem cell therapy for AMD within five years. The RPE cells, which support the photoreceptors, appear to hold the key to slowing the progression of AMD or reversing the damage. Surgical procedures already tested with a number of patients using their own stem cells have illustrated that cell replacement therapy can work. However, adult retinal stem cells do not appear to proliferate readily into RPE cells in sufficient numbers to make a difference. The team has succeeded in generating RPE cells from human embryonic stem cells, an achievement that makes clinical applications more feasible because of the large quantities of cells that would be necessary.
Scripps Research Unit in California is taking a different approach. It is focusing on repairing the new, abnormal blood vessels that develop in response to scarring or inflammation. This method uses adult stem cells harvested from the bone marrow of the patient. When these are injected into the eye, they become blood vessel cells (endothelial cells) which can stabilize the existing blood vessels that would otherwise degenerate in the eye. They also seem to have a role in rescuing nerve cells in the surrounding tissue.
This rescue effect may have implications for using stem cells to treat other eye diseases, such as retinitis pigmentosa which is a progressive eye disease affecting the rods and cones in the retina. Glaucoma, where increased eye pressure can lead to loss of neurons and eventually loss of sight, may also be helped by applying this principle.
A team in Scotland recently announced a small clinical trial in Edinburgh and Glasgow that will remove the limbic stem cells from the cornea of deceased donors to grow sufficient replacement tissue in the laboratory, which will then be transplanted onto the surface of the cornea of patients suffering with chronic corneal disease. This blends the traditional approach to treatment with stem cell technology to grow additional tissue.
A Canadian team led by Dr Valerie Wallace at the University of Ottawa is following the trails of both of the limbal and retinal stem cells, trying to crack the genetic code in the cell biomarkers that in many cases drives cell degeneration. If they are successful, they may be able to create cells that give instructions to reverse this process. However, in order to apply such discoveries to clinical practice, the team must determine in collaboration with biotech companies how to derive the large quantities of cells required for transplantation.
Many obstacles must be overcome before the therapeutic use of stem cells to treat eye disease is routine, but researchers agree that a cure for blindness may be on the horizon.
Canada
Dr Derek van der Kooy and his team at the University of Toronto were the first research group to isolate human retinal stem cells. They continue to investigate both how these cells develop and their therapeutic potential in animal models of human retinal disease.
Canadian research in the use of stem cells for treating eye diseases is now largely coordinated through the Stem Cell Network by Dr Valerie Wallace with support from Foundation Fighting Blindness. Multi-team collaboration is quickening the pace of discovery. “Biosynthetic corneas” manufactured for transplantation are in Phase 2 clinical trials. If successful, these surrogates have the potential to address the unmet worldwide demand for donor corneas, thereby restoring sight to a larger number of patients than is now possible.
Stem cell transplantation that has been shown to be feasible in the cornea may also be feasible in the retina. The strategy of the research team is to push forward perfecting the techniques they are using in the cornea, and then modify them for application in the more complex retina where photoreceptor replacement is the most likely way forward.
The search for the best source of the right kind of stem cell is the first challenge. Wallace’s team will compare using human embryonic stem cells (hESC) with a new process that clones hESC in the lab, called induced pluripotent stem cells (iPS). Because iPS cells are derived from a patient’s own tissue, this most promising technology avoids the ethical issues involved in using hESC, as well as providing a source of patient-specific cells for transplantation.
The second challenge is how to engineer a safe and sufficient supply of these cells for translating these discoveries to the clinic. By collaborating with a biotech company in California, significant progress is being made in this regard.
Websites
General Information
CNIB
Foundation Fighting Blindness
The Foundation Fighting Blindness (Canada)
The London Project (UK)
Macular Degeneration Partnership
National Eye Institute
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