Stem Cell Therapy to Cure Eye Diseases

Introduction

Stem cells are undifferentiated cells able to divide indefinitely yet maintain the ability to differentiate into specific cell types. They are able to survive throughout the lifetime of the organism, while maintaining their number, producing populations of daughter cells (transit amplifying cells) that can proceed down unique pathways of differentiation. Stem cells may be obtained from embryonic tissues, umbilical cord blood, and some differentiated adult tissues. Although the potential for stem cell-based therapies for a variety of human diseases is promising, numerous problems remain to be overcome, such as methods for obtaining, transplanting, inducing differentiation, developing function, and eliminating immune reactions. Stem cells have great potential value in treating eye diseases characterized by irreversible loss of cells, such as glaucoma and photoreceptor degeneration.

Although stem cells offer great opportunities for repair of the nervous system and the eye, their clinical use necessitates that we first gain an understanding of their proliferation, migration, differentiation, immunogenicity, and establishment of functional cell contacts. It will also be necessary to produce these cells in conditions that meet appropriate safety and effectiveness standards. Our current understanding of the critical factors affecting stem cell behavior remains limited. Rapid progress is being made, and some of the first applications of stem cells to wound repair in human eyes have produced successes that offer hope for the use of stem cells in other ophthalmologic conditions. Stem cells are very useful in ocular diseases, where nothing could be offered by conventional treatment.

Sources of Stem Cells

The best understood stem cells are embryonic stem cells, which derive from early fetal development. To our knowledge, human embryonic stem cells were first characterized in 1998. These cells are pluripotent (able to differentiate into a wide variety of cell types) and relatively easy to maintain in culture, but they are necessarily allogeneic (from a different genetic donor) to the potential recipient. Embryonic stem cells are continuous cell lines and have the potential to differentiate into retinal neurons, such as photoreceptors, so they might serve as an inexhaustible source of neural progenitors for stem cell therapy in the retina. Adult stem cells, as the name implies, are derived from mature organisms and are present only in restricted cellular compartments. They are multipotent (able to differentiate into a restricted number of cell types). Stem cells derived from the central nervous system (CNS) and ocular tissues have been identified as sources for cells that may someday be used to repair damaged brain, spinal cord, and retina. Stem cells within the eye have received attention because of the possibility that they could be obtained from a patient with eye disease and used autologously. Some of the probable sources for ocular stem cells are

• Limbal stem cells
• Conjunctival stem cells
• Retinal stem cells

The corneal endothelium may contain regions for storage (most peripheral), regeneration (paracentral), and migration of stem cells. An area of corneal endothelial cells adjacent to the Schwalbe line may be able to transit amplifying cells and slow-cycling cells.Endothelial cell density is markedly increased in this area, as compared with central endothelial cell density.

Differentiation of Stem Cells

To obtain large numbers of engrafted stem cells that differentiate in a desired way, strategies are needed to channel cells into desired phenotypes. Modification of the microenvironment and/or inhibition of intracellular signaling cascades in engrafted cells will be needed for appropriate cellspecific differentiation into injured tissue.

How stem cells offer hope in ocular diseases

Stem cells have great potential value in treating eye diseases characterized by irreversible loss of cells, such as glaucoma and photoreceptor degeneration. Ocular diseases, such as retinitis pigmentosa and age-retinitis pigmentosa and age-related macular dengeration, reflect damage to specific cells that are not normally repaired or replaced but they may be treated by stem cells transplantation.

Conditions that destroy the limbal area of the peripheral cornea, such as the Stevens-Johnson syndrome, ocular pemphigoid, and chemical and thermal injuries, can deplete stem cells of the corneal epithelium. The result is scarring and opacification of the normally clear cornea. Standard corneal transplantation cannot treat this form of functional blindness - stem cells have potential.

In some retinal diseases, photoreceptor cells die due to an intrinsic abnormality and/or due to disruption or death of supportive cells in the retinal pigment epithelium. However some other parts of the body can cope with similar cell death. This is because other existing cells in the tissue can divide in a regulated way to create new cells that replenish the remaining stock. Unfortunately, this is not the case for mature retinal photoreceptors. This is why stem cells might be very handy, because some of them do have the capacity to divide and form new photoreceptors. It is therefore hoped that they might be harnessed in the future to replenish the ailing retina of its photoreceptors.

They could be surgically transplanted into the eye or drugs could be developed to activate suitable populations of stem cells naturally present within the patient's body. With respect to transplantation, stem cells may be triggered to partially or fully specialise into photoreceptors in the laboratory before being transplanted into the eye. Once in the retina it is hoped that the new retinal cells will mature and incorporate within the existing tissue. This process may be helped naturally by the degenerating retina, which emits signals into the local environment of the eye, to indicate its state of damage.

Age related macular degeneration

Age-related macular degeneration (ARMD) is a degenerative condition of the macula. ARMD is caused by hardening of the arteries that nourish the retina. This deprives the sensitive retinal tissue of oxygen and nutrients that it needs to function and thrive. As a result, the central vision deteriorates.

Retinal stem cell research explodes the myth that macular degeneration is irreversible. These studies demonstrate that, in adult eyes, one can resurrect vision-related cells like photoreceptors and induce production of critical visual process dependent chemicals such as rhodopsin.

Glaucoma

Eye has pressure just like your blood, and when this intraocular pressure (IOP) increases to dangerous levels, it damages the optic nerve. This can result in decreased peripheral vision and, eventually, blindness. Glaucoma is similar to ocular hypertension but with accompanying optic nerve damage and vision loss.

There are at least three potential targets for stem cell therapy in glaucoma

• RGC
• Optic nerve head
• Trabecular meshwork

Stem Cell research in glaucoma mainly focused on replacing RGCs because their death is the final common pathway for visual loss in glaucoma and other optic neuropathies. HumanRGCsaremammalian CNS neurons that cannot divide and differentiate to replace other cells lost from disease. Blindness from glaucoma is irreversible. Finding a way to differentiate stem cells into RGCs and allow them to connect to their appropriate targets would be a major step in repopulating the neurons lost in glaucoma.

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is the name given to a group of inherited eye diseases that affect the retina. Retinitis pigmentosa causes the degeneration of photoreceptor cells in the retina. Photoreceptor cells capture and process light helping us to see. As these cells degenerate and die, patients experience progressive vision loss.

Derivation of retinal cells from human embryonic stem cells can be used potentially to treat retinitis pigmentosa. Loss of retinal vasculature is a presumed metabolic consequence of photoreceptor de-generation. Studies show that autologous bone marrowderived lineage-negative hematopoietic stem cells, which incorporate into the degenerating blood vessels in patients of retinitis pigmentosa, prevent cone loss. The use of autologous bone marrow might avoid problems with rejection.

Ocular Tumors

Benign and malignant cancers can sometimes attack the eyes. Left untreated, ocular tumors threaten not only a person's vision, but his or her life as well. Symptoms of eye cancer include blurry vision, distorted vision, blind spots, decreased side vision, white pupils, red eye, eye pain and complete vision loss. Sometimes ocular tumors present no symptoms at all.

Choroidal melanoma is a malignant cancer caused by uncontrolled cell growth within the eye. It occurs most frequently in patients 60 to 65 years old. Retinoblastoma, a cancer originating in the retina, is most common in children under five. Nationwide, over 500 new cases of retinoblastoma are diagnosed every year. Ocular cancers also include those that spread to the eyes from other parts of the body, especially breast, lung and bowel cancer.

Clinical use for adult stem cells has shown positive results in treating metastatic ocular tumors. The spreading ocular tumor has a poor prognosis with conventional treatments. Adult stem cells along with chemotherapy have been successful with different ocular tumors.

A localized retinoblastoma of the left eye in a 7-year-old girl, was treated by enucleation and received no additional therapy. Four months later, metastases of retinoblastoma in the lymph nodes, bone and bone marrow were diagnosed. Relapse chemotherapy consisting of three courses of vincristine, cyclophosphamide, etoposide and carboplatin led to a second complete remission. Subsequent high-dose chemotherapy with thiotepa, etoposide and carboplatin and autologous stem cell transplantation with CD34-selected stem cells were successful, with no adverse effects. No radiotherapy was given and the girl remains in continuous second remission with a follow-up of more than 4 years.

Stem cells in ocular surface disease

The corneal epithelium is a highly differentiated cell type with rapid self-renewal and limbal stem cells are primarily responsible for epithelial replacement and maturation. Any damage in limbus leads to variety of seemingly unrelated disease process under one heading of corneal stem cell disease.

The cornea is resurfaced by abnormal, injured conjunctival epithelium, after severe chemical or thermal injury to the eye. Such eyes are chronically inflamed and irritated with persistent epithelial defects, stromal scarring and neovascularization. Poor prognosis after conventional therapies led to use of alternative modalities.

Limbal stem cells under different conditions are used for transplantation in patients with grade III & IV chemical injury, recurrent pterygium and other ocular surface diseases.

Server ocular surface disease (OSD) with limbal stem cell deficiency is one of the most challenging disease entities facing the clinician today. Poor outcome with conventional treatment have been observed in these patients. Limbal stem cell transplantation has shown promising results in these types of cases. A variety of limbal stem cell transplantation options are available to replace defective limbal tissues.

Stem cell culture

There is ongoing research into the benefits of directly transplanting healthy photoreceptors taken from donor eyes. In fact, in animal models of retinal degeneration, such transplants have been observed to restore retinal structure somewhat. However, even if this approach can be perfected and shown to significantly restore vision in humans, there is one major problem. Just as the number of people requiring donor hearts far exceeds the number of organs available for transplantation, it is likely that more patients would benefit from retinal cell transplantation than available quantities of donor eye tissue will support. Unlike photoreceptor cells, stem cells can be helped to divide many times in the laboratory, thereby expanding the number of cells available for transplant and providing for the treatment of more patients. Stem cells can often be kept expanding for lengthy periods of time in the laboratory and they might, therefore, represent a renewable source of replacement cells.

Source

Invention Intelligence, September - October 2006