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Regenerative Medicine

Regenerative Medicine content

The retina is like a specialised part of the brain and unfortunately the cells that populate the retina, like the brain and spinal cord, have no ability to regenerate themselves. Often, in advanced stages of retinal disease, cells including retinal pigment epithelial (RPE) and photoreceptors have already degenerated.

In this scenario, due to the loss and absence of viable retinal cells, gene replacement therapy is unlikely to benefit patients. Therefore, the use of cell therapy holds great potential to preserve or restore vision in these individuals. Therapeutic stem cells being investigated in clinical trials include autologous bone marrow derived stem cells, human retinal progenitor cells, embryonic stem cell-derived RPE, induced pluripotent stem cell (iPSC)-derived RPE, and human central nervous system (CNS) stem cells.

In this section

 

What are stem cells?

Stem cells are cells produced in the body that when under the right conditions have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive.

When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialised function, such as a muscle cell, a red blood cell, or a brain cell or retinal cell (rods, cones and retinal pigment epithelial cells).

Adult stem cells

Adult stem cells are derived from foetal or adult tissue. Usually they can only give rise to the cells of that tissue. In some tissues, these cells sustain turnover and repair throughout life. For example, stem cells that are found in the skin will produce new skin cells, ensuring that old or damaged skin cells are replenished.

Embryonic stem cells

These cells are derived from a small group of cells (called the inner cell mass) within the very early embryo. Human embryonic stem cells are obtained from embryos that are 5-6 days old. At the stage that embryonic stem cells are derived, the embryo is called a blastocyst, and is no bigger than a grain of sand. Embryonic stem cells are able to form all of the different types of cells in the body.

Induced pluripotent stem cells (iPS cells)

In 2006, a group of scientists in Japan produced induced pluripotent stem cells (iPSC). Scientists found ways to turn ( re-programme) an adult cell such as a skin cell back into an embryonic-like stem cell. These are called induced pluripotent stem (iPS) cells. Six years later, this discovery was awarded the Nobel Prize in Medicine.

These cells are playing an increasingly important role in laboratory studies and are proving to be an ideal research tool. iPS cells derived from the skin of somebody with genetic form of sight loss will contain the mutation that caused their retinal condition.

If these iPS cells are persuaded to develop into retinal cells in the lab, researchers have an ideal cellular model for studying disease processes and experimenting with new treatments. Additionally, iPS cells can be manipulated to form retinal cells such as RPE which can then be transplanted into an individual with the hope of restoring vision.

Retinal progenitor cells

Retinal progenitor cells are early descendants of stem cells that have already started down the differentiation pathway of becoming retinal cells.

Human central nervous system (CNS) stem cells

Human central nervous system (CNS; which includes the brain and spinal cord) stem cells are neural stem cells which can generate certain types of cells found in the nervous system. These stem cells can be taken from the embryo (known as embryonic), foetal or adult brain.

It is important to note that the retina is a part of the nervous system and there is research to suggest that the cells generated by this stem cell could provide support to the retina.

Autologous bone marrow derived stem cells

Autologous bone marrow derived stem cells can generate many different types of cells of the nervous system. As the retina is a part of the nervous system, these stem cells could offer the potential to generate cell types which could support the retina. These cells could also provide other means of support, through their influence on the immune system (body’s own defence system) and their ability to promote the growth of blood vessels.

 

The Potential of Cell-based Therapies

Building on results from studies of retinal development and developmental biology in general, there is now great interest in the use of stem cells for the study and treatment of sight loss conditions. In 2018, approximately 20 early phase clinical trials involving cell-based therapy for degenerative retinal disease were underway.

There are currently two different strategies being explored – to repair damaged retinal cells or to protect what is remaining.

The first approach aims to repair or replace damaged retinal cells, either through the transplantation of retinal pigment epithelial (RPE) or the transplant of photoreceptors. Transplantation of photoreceptors cells (rods or cones) has proved more challenging, but as scientists continue to understand mechanisms behind developmental biology and with advanced technologies, this is an area that will continue to progress over the coming years.

As a result, much focus has been dedicated to the transplantation of RPE cells. In fact, there are a number of early stage trials which are testing this approach for late-stage Age-related macular degeneration (AMD), Retinitis pigmentosa (RP) and Stargardt disease.

In 2018, a clinical trial which took place in the UK published promising preliminary data. The aim of this study is to replenish damaged retinal cells by inserting a ‘patch’ of new cells into patients with severe wet-AMD. Retinal pigment epithelium (RPE) cells, which provide critical support and nourishment to our photoreceptor cells were first generated from embryonic stem cells.

This layer of new RPE was then placed on a specially engineered patch so that it could be easily transplanted into the back of the eye, an area known as the subretinal space. Two patients, who both had severe form of wet-AMD were treated using the stem cell based patch and monitored over 12 months.

In this recent publication, investigators reported the successful delivery and survival of the patch. Both patients also reported improvements in sight as measured by their ability to read letters off a chart (Snellen chart).

There are also a number of clinical trials exploring the potential benefit of retinal progenitor cells (hRPCs). These are stem cells that have partially developed into retinal cells. One example is the Phase I/II clinical trial (Clinicaltrial.gov identifier: NCT02464436) taking place at Massachusetts Eye and Ear Infirmary for late-stage Retinitis pigmentosa.

The treatment involves the subretinal injection (under the retina) of human retinal progenitor cells (hRPCs). Based on results from pre-clinical studies, researchers believe the injected hRPCs will integrate into the retina and fully develop into photoreceptors, replacing those lost to disease and, thereby, restoring vision. They also believe the treatment will protect the patient’s retina from further photoreceptor loss.

In 2019, researchers at NIH’s National Eye Institute (NEI) developed protocols for producing an autologous induced pluripotent stem cell-derived therapy for dry age-related macular degeneration. NEI’s therapy would involve subretinal transplantation of a patch of iPS cell-derived retinal pigment epithelial (RPE) cells grown on biodegradable scaffolds. The research team showed that RPE cells in the AMD patient-derived patches were morphologically and functionally mature and that subretinal transplantation of the patch prevented photoreceptor cell loss in a rat model of AMD.

A second approach mentioned earlier aims to protect or preserve remaining retinal cells. An example of this is a Phase I/II clinical trial in the United States (Clinicaltrial.gov identifier: NCT03073733), which is looking to improve vision primarily through a protective route but also possibly replacement in end stage Retinitis pigmentosa (RP). The therapy involves the injection of retinal progenitor – stem cells that are in the process of becoming retinal cells – into the vitreous, the gel-like substance in the middle of the eye.

Researchers believe the cells will release proteins that will keep the patient’s existing photoreceptors healthy, preventing their degeneration and preserving vision. Investigators also believe the proteins might rescue cones that have stopped processing light, but haven’t fully degenerated. Cones are the photoreceptors that provide the ability to read, recognize faces, and see in lighted conditions.

IMPORTANT: We caution people to be careful about clinics that promise cures from stem cells. Many of these are largely unregulated and could pose huge risk to patients. Additionally, if a clinic is charging for a stem-cell treatment or procedure for your condition, it is probably not legitimate.

If you have any questions about the legitimacy of a stem-cell clinic, trial, or alleged therapy, please speak with your ophthalmologist or contact us at research@fightingblindness.ie.

 

The Future for Cell-based Therapies

Whilst regenerative medicine holds great potential, further research is required to address some of the challenges and unknowns associated with cell transplantation. These include:

  • What type of stem cell and stage of maturity will work best?
  • The need for greater safety and efficacy data over a longer period of time
  • Efficient integration and development of synaptic connections and functionality
  • Effective mode of delivery of stem cells e.g. matrix, bolus, and scaffold
  • Three-dimensional retinal organoid technology

In recent years, a new form of stem cell research has surfaced and it is transforming the study and treatment of retinal diseases. We have recently seen a ‘boom’ in organoid research. This means it is now possible to create miniature human retina from stem cells in a laboratory dish.

These are basically ‘mini retinas in a dish’. Using carefully timed chemical cues, researchers can build three-dimensional structures that resemble the retinal layer found at the back of the eye.

Tissues developed in this way are often referred to as organoids because although they are not quite organs yet, they can mimic some of the structure and function of real organs. In this case ‘mini retinas’ created in a dish are extraordinarily similar to human retinal cells able to grow and respond to light in much the same way as the human retina does.

Researchers can generate mini retinas in a dish directly from a person affected by retinal disease. Scientists for example have encouraged iPS cells derived from patients affected with retinal degenerations such as Stargardt disease to form into mini retinas.

By doing this, it opens a lot of possibilities in order to understand the mechanisms that cause disease much better. The work not only advances opportunities for vision saving research but may lead to technologies that can restore vision in people with retinal diseases.

To learn more about cell therapies, please contact research@fightingblindness.ie or ring 01 6789004.

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