Stem
cell research is being used in South Africa to develop “disease in the dish”
models that fix a gene mutation that results in night blindness, tunnel vision
and eventually blindness.
If the
research pans out, the mutations can be fixed in a process called gene editing,
which takes place in stem cells derived from the patient’s skin. These stem
cells are turned into the tissue compromised in disease, which in this case is
the retina of the eye.
It is
the first step to understanding how mutations cause disease and whether
repairing the defect in the cell may reverse the disease process in a dish
model.
Although
these stem cell transplants have taken place in some parts of the world, they
are still in the clinical trail phase in North America. The research is among
the most advanced developments in stem cell treatment.
Night
blindness, tunnel vision and eventual visual impairment are symptoms of a
disorder called retinitis pigmentosa – one of several inherited eye diseases,
or retinal degenerative disorders.
Retinal
degenerative disorders occur in one in every 3500 people across the globe. But
these disorders are both genetically and clinically diverse. This is because
they are associated with mutations in more than 280 genes. The disorders can be
passed down from generation to generation through one or both parents and can
impact on the children differently depending on their sex. At least 50% of
cases are sporadic.
It may
occur with no other clinical findings or it may manifest as part of another
disease, such as Usher syndrome, where it is combined with hearing loss. This
is linked to the neurosensory or developmental abnormalities. It can also occur
as a result of other systemic diseases such as some forms of diabetes.
Understanding
the gene
Our
research looks at the mechanisms of one gene which causes night blindness and
peripheral vision loss. Understanding the mechanism is the first step to devise
any treatment for the disease.
The
gene, which we identified in 2004 (PRPRF8), is involved in the normal
functioning of the machinery involved in translating proteins in our bodies. It
is found throughout the body but in people who have a mutation it leads to
compromised vision.
Ideally,
to find the way to treat this disease, mutations that cause night blindness and
peripheral vision loss, we should work on a patient’s retina. But this tissue
is not available from living subjects.
This is
where stem cell research comes in. Stem cell research has been instrumental in
“disease in a dish” modelling to study a disease of interest or to create an
environment to test treatments for the disease. Whether or not a disease can be
treated depends on the understanding of the basic biology of the disease.
Disease modelling allows scientists to explore how a disease works in the
laboratory rather than directly on a patient.
A
disease in a dish
A
disease model represents the abnormal human biology in a particular disease.
Although mice have been used for disease modelling, researchers are moving
toward using cells in a dish because mice have ethical limitations and can’t
fully mirror human diseases.
There
are three different types of stem cells: adult stem cells, multipotent
mesenchymal stem cells and pluripotent stem cells.
Induced
pluripotent stem cells are adult stem cells that are reprogrammed in the
laboratory to behave like embryonic stem cells. These cells can be
differentiated into many tissue types, which can, theoretically, then be used
to treat various diseases.
By
making the induced pluripotent stem cells into cellular models for the
diseases, it allows researchers to study the effects of certain treatments on
the tissue, and this could include either gene editing or gene therapy studies
in vitro.
One
part of our study uses stem cell technology to harvest easily accessible skin
tissue from patients or their unaffected siblings and then grow these into
fibroblast cell lines which can be reprogrammed into induced pluripotent stem
cells.
These
reprogrammed stem cells are very similar to embryonic tissue which then have
the potential to be differentiated into photoreceptor and retinal pigment
epithelium cells.
Once we
have the photoreceptor and retinal pigment epithelium cells we will perform
human genome-wide gene expression. This is the process where genetic
instructions are used to make a gene product (transcriptome) analysis. This
analysis will shed light on the downstream effects of the mutation, and
possibly lead to an understanding of why retinal cells manifest the disease
rather than other cells, tissues or organs in the body.
The
model must reproduce aspects of the disease outside the body. This is quite
useful for diseases in which it is difficult to obtain the diseased tissue from
the patient such as retinal diseases.
This is
because retinal tissue or eye tissue cannot be obtained while the patient is
alive. If a person dies there is a limited time frame to collect the tissue.
Using the disease in a dish model eliminates these drawbacks.
The
link between stem cells and gene correction
If the
mutation is corrected in a disease in the dish model, via technology called
gene editing, it means that the corrected gene, without its mutation, can
theoretically be transplanted into the patient.
This
technology provides the promise for treating genetic diseases by transplanting
the patient’s own genetically corrected human induced pluripotent stem cells.
The
potential benefits of stem cell based gene therapy and gene correction are:
- eliminating the need for immunosuppression;
- the ability to generate an unlimited supply
of patient-derived transplantable cells; and
- the ability to gene edit the disease
causing genetic mutations.
In
South Africa researchers are working on gene editing and stem cell technology.
However, this is not at the clinical trial or therapeutics phase.
Although
clinical trials have started in some countries, this type of research is still
in its infancy as there are many obstacles before the use of stem cell based
gene therapy arrives in the clinic.
These
challenges include determining the safety and efficacy of this type of
treatment as long term results are currently unknown.
The
patient-specific retinal tissue in a petri dish gives us the potential of doing
sophisticated gene editing work. Although this can lead to reversing a cellular
disease in a dish, it is hoped to provide insights into our longer term
objective of disease-based therapeutics in humans.