1. Introduction
Every day in life we encounter different experiences; from tasting your first ever alcoholic
drink, smelling something burning , touching your lovers hand , hearing someone say I love
you or one of the most memorable moments for the majority of people; seeing a new day.
However, some do not, at least 39 million people worldwide are blind. It is suggested that
80% of all cases of blindness in adults is treatable (World Health Organisation, 2012). This is
at least 28,800,000 people’s lives that could be drastically changed and improved.
Glaucoma has been named as the second leading cause of blindness after cataracts. This
raises the urgency for a long term and efficient procedure for the treatment of glaucoma
because unlike cataracts glaucomatous vision loss is irreversible (World Health
Organisation,2004) . It is this increasing number of people losing their sight and likely to
never regain it that has led people to study whether stem cells could be used to treat
primary open-angle glaucoma and the likelihood of this treatment becoming available to the
general public within the next five years. “As a population grows older, the prevalence of
glaucoma rises” (World Health Organisation, 2004) increasing the need for assistance from
healthcare providers.
Primary open-angle glaucoma is the simplest, form of this condition, which is caused by
various factors, the most common being: raised intraocular pressure and ageing. Recently
there have been some advances in the technology and method of treating glaucoma; most
recently that allows fluid to be drained from the eye thus relieving pressure using a stent.
The procedure has been described by a consultant at the Birmingham and Midland Eye
Centre as a “significant advance” (BBC News, 2013). However it is hard to ignore the
advantages and life changing results that would come from the application of stem cells to
treat glaucoma when current studies have been conducted in their use for other
degenerative conditions such as Parkinson’s disease, “Stem cells to make better and safer
dopamine-producing nerve cells” (Wood, 2012) and dementia, “Using stem cells to
understand dementia with Lewy bodies” (Kunath, 2012).
However there are challenges to be overcome before this wonder treatment can be applied
into clinical trials and save the sight of millions. The science, policy and ethics surrounding
the use of stem cells still present many challenges (Fischbach and Fischbach, 2004). Early
diagnosis of glaucoma is difficult, hindering the successful preservation of sight (Johnson,
Bull and Martin, 2011).

2. Glaucoma and StemCells
Glaucoma is characterised by the progressive death of retinal ganglion cells and
degeneration of their axons which relay visual information to the brain via the optic nerve
from the eye (Johnson, Bull and Martin, 2011).The increased pressure within the eyeball can
cause a gradual loss of sight; globally it is a major cause of blindness with over 60 million
people suffering from it. In this report the form of glaucoma I will be focusing on; as there
are many variants of the condition, is primary open-angle glaucoma. Primary open-angle
glaucoma occurs when the eye’s drainage canals become blocked over a period of time and
inner eye pressure rises because fluid cannot drain out of the eye in the correct amounts.
(www.glaucoma.org). Unfortunately it is painless and most people have no early warning
signs of the condition or any visible sight loss .This can have detrimental effects, because if
left untreated glaucoma can cause complete blindness. Furthermore because neural retina
and the optic nerve are considered “implastic and incapable of regeneration” vision loss by
glaucoma is irreversible (Paul A. Sieving., 2012) (Johnson, Bull and Martin, 2011).
Stem cells are undifferentiated cells that possess the ability to self-renew indefinitely and
differentiate into any cell type within the human body. Therefore stem cells have the
potential of being used for cell-based therapies (Jayaram et al 2011). Stem cell therapy may
provide a promising new treatment for incurable degenerative conditions especially
glaucoma.
Science
There are many different types of stem cells, derived from different sources therefore the
ideal candidate for a stem cell based therapy would have to be: “readily available, easy to
expand in culture, possess an acceptable long term safety profiled, autologous in nature”.
At present there are no stem cells that meet all these requirements (Jayaram et al 2011).
From the research conducted at UCL Institute of Ophthalmology & Moorefield Eye Hospital
it seems there are possible candidates but each with their own limiting factors. For example,
embryonic stem cells which would be the ideal candidate are not readily available,
autologous in nature or have a clear validation of being safe because of their pluripotency -
they could result in the formation of cancerous cells (Jayaram et al 2011).
This does not mean that embryonic stem cells as a whole should be completely ruled out
and not considered as the possible candidates. Like most things in life there are solutions
and compromises that can be made and the potential for stem cells is too great.

3. There are three main categories of stem cells: embryonic, induced pluripotent and adult
derived stem cells.
Human Embryonic Stem Cells (ESC)
Embryonic stem cells are derived from embryos that develop from eggs fertilised in an in-
vitro fertilisation clinic then donated for research, with the donors consent.
They possess the ability of differentiating into any cell type within human body and have the
capacity for self-renewal. They would be ideal candidates because of their ability to migrate
and differentiate. In some studies they have been successful in differentiating the ESC’s in
vitro, (meaning that they were cultured outside the organisms’ body in an artificial
environment) into neurons and retinal ganglion cells. However, they have proven to be
limitations as it has been challenging to control differentiation which involves complex
laboratory protocols. Additionally because of their pluripotency, there is a risk of formation
of teratomas – teratoma is also known as a germ cell tumour which “contain components of
the three embryonic germ cell layers (ectoderm, mesoderm and endoderm)” (M.A Hayat
2012).
Further limitations are the ethical objections because of the creation and destruction of
what is considered human life. Embryonic stem cells would be the preferred and ideal
source of stem cells however because of the controversies regarding their use alternatives
to embryonic stem cells have had to be considered (Jayaram et al 2011).
Adult tissue derived stem cells:
These are an alternative to ESC’s which have various possible sources that have been
investigated to potentially regenerate retinal neurons such as Muller stem cells,
Mesenchymal stem cells and Oligodendrocyte precursor cells.
The advantage with the use of this type of stem cell is that it does not bring with it ethical
controversies (Jayaram et al 2011).
Muller stem cells can generate glia and new neurons, Müller glia are the radial glia, which
are an important cell type in developing the central nervous system. They have also been
shown to share a common derivation with retinal neurons. Mesenchymal stem cells are
commonly acquired from the bone marrow and umbilical cord blood which makes them
possible candidates for autologous cell transplantation. This ideally means the risk of
rejection and need for immunosuppressant’s is reduced significantly.
Oligodendrocyte precursor cells have been reported to “exhibit some stem cell
characteristics and neuroprotective potential in vitro” (Jayaram et al 2011). This makes
them potential candidates as a stem cell-based therapy to treat glaucoma.

4. Induced pluripotent stem cells (iPS)
Induced pluripotent stem cells which can be obtained from fibroblast cultures cannot be
differentiated embryonic stem cells. This means that you can obtain a cell that offers the
advantages of embryonic stem cells but without the ethical limitations. However before
they can be applied to human therapies further investigation must be conducted regarding
safety concerns; reactivation of pluripotency, characterisation and possible changes in
target cells must be confronted.

5. Methodof Treatment
Primary open-angle glaucoma cannot be prevented or stopped instead its progression can
be slowed down. The main method of treatment has been the administration of medication
and in some cases surgery if it is required. Eye drops are prescribed by doctors to control
intraocular pressure (IOP) within the eye; these may be uncomfortable and cause a burning
sensation (http://www.glaucomafoundation.org, 2013). However eye drops may not be
effective enough and the patient may then be prescribed with pills, such as beta-blockers
which act to lower IOP as well (Noecker, 2006).
However these methods of treatment may have unwanted side effects that minimize
convenience and comfort for patients. Surgery is usually the last option suggested by
doctors after medications have not worked, one of the forms of surgery is laser surgery
which can take up to 10 – 15 minutes and also acts in hoping to lower IOP
(http://www.glaucomafoundation.org, 2013). The patient may still need to take medication
even after going through surgery. There has been speculation in alternative treatments of
glaucoma to supplement the more traditional treatments available. Marijuana can
significantly lower IOP and the Ginkgo biloba which may have beneficial effects on glaucoma
(Rhee et al. 2001) but there is no supportive data for these recommendations.
These are all temporary solutions into treating glaucoma as long term results are not
available and no cure for glaucoma has been found. Stem cells may hopefully offer a ‘cure’
for glaucoma and provide long term treatments.
Currently the only stem cell-based therapy for the eye that has been proven to work in
clinical trials is the repairing of the cornea using limbal stem cells from the edge of the
cornea. Limbal cells from the corneal limbus are obtained and grown in a laboratory,
wherein the limbal stem cells are then transplanted onto the diseased cornea.
(EuroStemCell, 2012). However, this method does have its limitations as the numbers of
cells that can be obtained from the patient are very low and donors are in short supply. The
use of donors might also result in the decrease in success rate and long term efficacy due to
possible rejection (EuroStemCell, 2012).Further limitations are the methods adopted by
researchers when growing the cells in a laboratory and techniques in transplantation, which
could be improved.
The suggested approach for treating glaucoma using stem cells is to obtain stem cells,
preferably embryonic or induced pluripotent stem cells: culture of stem cells with the
appropriate growth factors in a laboratory; controlled differentiation of cells into retinal
ganglion cells and then their transplantation into the eye (EuroStemCell, 2012).This
approach is similar to one that is currently under study for Stargardt’s macular dystrophy. If

6. this trial is successful then the likelihood of this approach being transferrable for glaucoma
is very high.
The diagram below shows the replacement of retinal pigment epithelial cells. Techniques for
growing cells for therapies are being researched and tested in early clinical safety trials.
Replacing retinal pigment epithelial cells:
The transplantation of retinal ganglion stem cells into the eye could alleviate the effects of
glaucoma either by the replacement of retinal ganglion cells or neuroprotection (Johnson,
Bull and Martin, 2011).
Retinal Ganglion Cell replacement
The strategy into which stem cells could be applied to restore glaucomatous vision loss is
the replacement of retinal ganglion cells (RGC’s) (Cho, Mao and Klein, 2012) but to make the
replacement strategies successful, the number of cells needed to be transplanted has to be
restricted because of low stem cell supplies, therefore early intervention is necessary
(Jayaram et al 2011).
A vital requirement for RGC replacement is the differentiation of stem cells and
development of reliable protocols in which stem cells are directed to differentiate into RGC
precursors or mature RGC’s. At present there is research focused on the “identification of
suitable cells, which can be differentiated towards RGC’s and their precursors and the
experimental conditions required for optimal expression of their molecular markers”
(Jayaram et al 2011). this is a supportive statement; “convincing in vitro differentiation of
mature RGC from a suitable precursor cell type has yet to be demonstrated” (Johnson, Bull

7. and Martin, 2011).Previously there has been some evidence showing the efficient
generation of retinal progenitor cells from human embryonic stem cells (Lamba, Karl, Ware
and Reh, 2006) but it is still currently unclear what would be more advantageous: neural or
retinal stem cells, RGC precursors or mature RGC’s due to the lack of long term studies
showing successful and efficient integration. To date embryonic stem cell derived neural
progenitors have been shown to successfully generate retinal ganglion cells which in turn
could be used to treat neurodegenerative conditions like glaucoma (Jagatha et al, 2009).
Instead it is suggested that an immature but committed cell type might perhaps integrate
better with an existing retinal system (Johnson, Bull and Martin 2011).
At present the steps required for this method to be successful have not been considered
carefully, the approval and establishment of stem cell based therapies requires strict
protocols for safety and efficacy thus making the idea of RGC replacement as “science
fiction” (Johnson, Bull and Martin, 2011). A more recent study was carried out on the
comparative analysis of targeted differentiation of human induced pluripotent stem cells
(hiPSCs) and human embryonic stem cells. Using independent protocol they found that cells
differentiated from hESCs and hiPSCs showed functional similarities and similar expression
of genes characteristic of specific cell types (Toivonen et al, 2012).
Neuroprotection
Another possible method stem cell based therapy could become available is via
neuroprotection, which is the preservation of vision. From the name of the treatment you
can identify that for it to be successful that early diagnosis of glaucomatous vision loss is
essential. It would only be successful if photoreceptors can still functionally respond to light
(Thumann, 2012). It is hypothesized that stem cells could be transplanted to achieve retinal
ganglion neuroprotection in glaucoma as they could activate neuroprotective pathways
(Johnson, Bull and Martin 2011).Furthermore stem cells can generate neurotropic factors
and other aspects of CNS environment that help endogenous healing within a cell.
Neurotropic factors would aid the growth, survival and development of neurons while
maintaining existing ones. Oligodendrocyte precursor cells have been suggested as a
possible cell type that could be used to offer this protection (Vasudevan, Gupta and
Crowston, 2011). This method of treatment could be possible via the transplantation of
stem cells within an encapsulation device; these devices would limit and possibly reduce any
possible chance of an immune attack on the stem cells thus making the efficacy of the
treatment long term. However to date there are no such proven treatments for glaucoma
(Johnson, Bull and Martin, 2011).
Research has been conducted into the neuroprotective effects of mesenchymal stem cell
(MSC) transplantation in experimental glaucoma. MSC’s were isolated from the bone
marrow of a transgenic rat and transplanted into the trabecular meshwork. Optic nerve

8. damage was then assessed 4 weeks after transplantation. Results showed that the MSC’s
could survive for at least 5 weeks and there was a significant increase in the survival of RGC
axons, this shows that transplantation of MSC’s was successful and neuroprotective in a rat
glaucoma model. Further research should be conducted in their possible use for cell based
therapy in glaucoma (Johnson, Bull, Hunt, Marina, Tomarev and Martin, 2010). A further
study went on to validate that the neuroprotective effects of RGC-protective therapies
could be replicated in adult retinal explant culture (Bull, Johnson, Welsapar, DeKorver,
Tomarev and Martin, 2011).
Another study on the long-term survival and differentiation of retinal neurons derived from
human embryonic stem cell lines in un-immunosuppressed mouse retina and showed the
successful integration of photoreceptors into the RGC layer. The study was able to “provide
new insights into the technical aspects associated with cell-based therapy in the retina”
(Hambright, Park, Brooks, McKay, Sawroop and Nasonkin, 2012).However it seems that
there still areas that require further research and consideration in the successful and
functional outcome of stem cell based therapies becoming available for clinical trials.
“Clinical translation of preclinical studies evaluating stem cell-mediated neuroprotection for
glaucoma is presently limited by various experimental shortcomings including relatively
short durations of published experiments” (Jayaram et al 2011).
StemCell Ethics and Policy
A major limitation in the further application of stem cells in preclinical and clinical studies is
the ethical controversies they carry. The stem cells are obtained from a blastocyst which is a
4-5 day old embryo formed prior to implantation in the uterus and consists of a hollow mass
of only a few undifferentiated stem cells (Fischbach and Fischbach, 2004). This gives rise to
the moral status of embryos and whether they should be protected by the same laws that
protect humans (Fishbach and Fishbach, 2004). This is the fundamental argument of those
who oppose destruction of embryos. The main opposition usually comes from religious
groups: Catholicism, Hinduism, Islam, Judaism and Lutheranism (Mlsna, 2010). They try to
justify that life begins at conception (Fischbach and Fischbach, 2004).
People’s opinions on the moral status of embryos can usually be divided into three different
views.
 Stem cells are only a small collection of cells therefore placing embryos in the same
ethical or moral significance as a sample of blood, therefore “deserve little or no
special treatment” (Mlsna, 2010.)

9.  Embryos have a greater standing than a collection of cells but not as significant as
that of a fully developed human being, thereby granting some ‘special treatment’
but not nearly as much as of a human being.
 Embryos possess the potential of forming into a human being therefore their status
is equivalent to that of a human being.
However those opposing this would argue that human life “develops by degrees… beings
capable of experience and consciousness make higher claims” (Sandel and Phil, 2004). This
means that value is placed on their structure rather than their function (Fischbach and
Fishbach, 2004). An analogy that could be applied to this is that an acorn is not an oak tree
(Sandel and Phil, 2004).Another argument for the use of stem cells and how their
advantages outweigh the disadvantages is that the sacrifice of a foetus, which has the
potential of becoming a person, could be morally justified in order to rescue the life of
another person (Wert and Mummery, 2003). But this could be deemed as unjustified and
likened to the experiments of Nazi doctors on prisoners. Although they resulted in
discoveries that alleviated human suffering they cannot be morally justified (Sandel and Phil,
2004).
A different stance from those opposing research on embryos is that it is seen as too
dangerous or ‘playing God’. However these were the same perceptions people had on heart
transplants and IVF both of which now have wide spread approval globally.
Other people view sanctioning stem cell research as a slippery slope towards Godlessness
(Criswell, 2005).In addition to this there is the feminist perspective to consider as women
would be the sources of ova for stem cell production (Holm, 2002). Therefore can it be
morally justified if it has no benefits, induces the unpleasant treatment and possible
detrimental effects on the health of the donor. There are possible risks that may arise from
multiple egg extraction such reproductive cancers and infertility
(http://handsoffourovaries.com). There are possible short and long term effects that could
result from drugs used to suppress ovaries. These must be identified and studied as they
could result in: formation of blood clots that might potentially cause damage to vital organs,
depression and ironically vision abnormalities (Norsigian, 2006). Stem cells offer great
promises for the development of therapies and treatments for chronic diseases that are
currently unavailable but how are we to “redeem the great biomedical promise of our time”
(Sandel and Phil, 2004).
In 2001 President George W. Bush restricted federal funding for research on stem cells
obtained from human embryos because it required the destruction of human life. It
permitted the funding to already existing cell lines only. He said in his speech “My position
on these issues is shaped by deeply held beliefs,” “I also believe human life is a sacred gift
from our creator.” (Park, 2012). However offering religious opinions cloaked in scientific
language and veneers is dangerous (Fischbach and Fishbach, 2004).Stem cell debates have
helped to reveal the complicated relationship between science and politics (Witherspoon

10. Council, 2012). Scientists had to gain funding from businesses, private foundations or other
philanthropic sources which can prove to be very difficult as they require vast amounts of
money. “£2.6 million is being invested in the development of stem cell therapies for…
glaucoma and diabetic retinopathy” (Conroy, 2012). However in 2009 President Barack
Obama lifted the restriction making it possible for scientists to gain federal funding to use
embryos from IVF procedures to obtain stem cells for study (Park, 2012). President Barack
Obama said “This order is an important step in advancing the cause of science in America”
(U.S News, 2009).
Stem cell regulations in other parts of the world:
Europe - In the United Kingdom research on human embryos is allowed for certain
purposes such as to increase knowledge to be applied in developing treatments
for serious disease but it requires a license from the Human Fertilisation and
Embryology Authority (EuroStemCell, 2011).
- Research can only take place on embryos up to 14 days old this allows ethical
validation (Fischbach and Fishbach, 2004).
Germany, Austria, Italy, Finland, Greece, Ireland, Portugal and the Netherlands
prohibit or severely restrict the use of embryonic stem cells (EuroStemCell, 2011).
Africa - South Africa permits the creation of human embryos for research and
reproductive cloning is banned, however therapeutic cloning is permitted.
Research is allowed on embryos and zygotes no more than 14 days old (National
Health Bill, 2004).
Asia - South Korea allows the utilisation of stem cells for research to diagnose, prevent
or treat diseases (Bioethics and Safety Act, 2008).
Reproductive cloning is banned whereas therapeutic cloning is permitted and still
pursued (Dhar and His-en Ho, 2009).
- China prohibits any research on human reproductive cloning.
Research using human embryonic stem cells derived from a blastocysts, IVF or
foetal cells from voluntary abortions is permitted (The Ministry of Health of the
People's Republic of China, 2003).
- Japan allows stem cell research for therapeutic purposes however there are still
no formal regulations (Dhar and His-en Ho, 2009) however The Ministry of Health,
Labour and Welfare is working to amend guidelines regarding stem cell therapies
(Martell, Trounson and Baum,2010).
Oceania - New Zealand has very restrictive guidelines on stem cell research, while research
for adult stem cells is permitted that involving human embryos is very restrictive
and it has published ‘Guidelines for Using Cells from Established Human Embryonic
Stem Cell Lines for Research’ which provides criteria that must be met (Australian
Society For Stem Cell Research, 2009).
Research on ‘non-viable’ human embryos is permitted but not ‘viable’ human
embryos (Human Assisted Reproductive Technology Act, 2004).

11. Steps towards Clinical Trials
After basic research has been carried out on the efficacy of stem cells in models and ethical
issues have been identified and minimised. The next stage before a clinical study can be
carried out is pre-clinical work. The work must be peer reviewed by experts, follow
regulations, gain approval and lastly gain consent of patients (www.optistem.org, 2011).A
clinical trial is the scientific investigation of a new treatment that has shown some benefit in
animal or laboratory studies, but that has not yet been proven effective in humans
(dictionary.reference.com, 2013). Treatments mustbe tested in clinical trials before they can be
made available to the general public, to ensure safety,feasibility and efficacy. The sample of people
selected must be healthy and their medical records are reviewed to eliminate any factors that
might affect the results of the trial. This sample could vary in age, gender and ethnicity.
Clinical trials consist of four phases:
 Phase I trials check on safety to make sure the treatment is not harmful to patients
with around 20 – 80 participants (EuroStemCell, 2013)
 Phase II uses a larger sample of people of 100 - 300
 Phase III or IV trials assess the effectiveness of the treatment and developing it
into a therapy that can be made widely available using a sample of 1,000 – 3,000
people (EuroStemCell, 2013).
It's the clinical trials that take so long, usually several years but once they have undergone
Phase IV the benefits of waiting are phenomenal.

12. Evaluation
What is the likelihood of stem cells being used to treat primary open-angle glaucoma within
the next five years? It has been shown that current treatments for glaucoma are insufficient
and using stem cells to protect against further vision loss is potentially feasible and their
benefits would be highly advantageous for patients. The potential that could be obtained
from these stem cells is limited due to their different ethical views in society, furthermore
due to a lack in the number of stem cells available this might prove to be another limiting
factor as gaining funding can prove to be quite difficult. However although the ethics and
laws regarding the use of stem cells might initially be considered to be a major factor
hindering the advance of stem cell based therapies for glaucoma. The laws and regulations
around the world have been shown to be reasonable enough to allow research in order to
prevent or treat a disease. Therefore the barriers in practise of actually using stem cells are
not as big as finding a source for stem cells.
Luckily because of this further studies into the use of neuroprotection can be carried out.
There have been uncertainties with this method such as: trying to make the regenerated
cells have functional outcomes when they route all the way back to the brain and the
conditions in which this takes pace, ideally being at an early stage of glaucoma so as to
reduce the number of dead optic nerve cells. Recently died optic nerve cells are also more
favourable as the signposts to route information to the brain may still be there. Retinal
ganglion replacement has also been shown to be a viable method of treatment; however its
limitations are somewhat more serious than that of neuroprotection as there are not
enough long term studies showing the efficacy of this method. In addition to this there are
concerns regarding safety as there is a risk of teratoma formation is possible. This is highly
undesirable as it would put glaucomatous vision loss patients in a far worse position than
before. These limitations and risks must be further studied to ensure they are as low as
reasonably possible.
Therefore the evidence within the report is supportive in proving that there is a valid
probability of stem cells being used to treat primary open-angle glaucoma. The studies
carried out were by various scientists and all of high credibility. Their work is also recognised
internationally by scientists within this field and proven to be accurate and reliable.
However regarding the time period into which this can be done it is unclear whether it can
be done in five years is quite unclear not only due to some missing areas of research but
also ethically. Some of the research included bias views of different groups of people and
this was necessary in order to show that there are strong views of opposition to the use of
stem cells that need to be overcome. All of the research and studies can be critically
assessed to find very little fault or error in showing the likelihood of stem cells being used
to treat primary open-angle glaucoma within the next five years.

13. Conclusion
To conclude I believe that the likelihood of a stem cell based therapy becoming available for
glaucoma is possible but not within the next five years because it will be some time before
these therapies are even approved for clinical trials. In addition to this the clinical trials
would take further time and prolong the time before a therapy was made available to the
general public. Therefore in my opinion, the likelihood of stem cells being used to treat
primary open-angle glaucoma within the next five years is relatively low but the probability
of it being capable of happening in the next 10 – 15 years is high enough to assure
glaucomatous vision loss patients of very promising results in the future.
Natasha Madzingira