Stem Cells

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• Overview
• Type of stem cells
• Stem cells as a potential treatment for eye diseases
• Is it safe?
• Beware of unregulated “stem cell trials”
• Limitations
• References

Overview

Stem cells are cells in the body with the following characteristics:

• Ability to develop into different specialised cells types in the body such as the photoreceptors in the retina, liver, nerves and muscles
• Unlimited self-replication/self-renewal (ability to divide over and over again to produce new stem cells)

These inherent abilities, coupled with an increasing understanding of cell culturing, have made stem cells an attractive option in various facets of eye research which include:

• Understanding the mechanism of a specific condition by culturing cells harvested from a patient and growing them into little “eye cups”
• Facilitates the identification and testing of new drugs for a specific condition before proceeding to clinical trials
• Replacing or regenerating damaged retinal cells

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Type of stem cells

Stem cells can be broadly classified into two types, embryonic and adult stem cells. Human embryonic stem cells (hESCs) are obtained from unused embryos during in vitro fertilisation (IVF) procedures. These cells are donated to science with the consent of the involved parents. ESCs are able to transform into virtually any cell type in the body (pluripotent).

hESCs have always been the main source of pluripotent stem cells until the discovery of human-induced pluripotent stem cells (hiPSCs).^[1] iPSCs are generated by reprogramming mature cells (usually skin or blood cells) into pluripotent stem cells. After that, the IPSCs can be directed into becoming any cell type of interest.  In essence, we could generate our own pluripotent stem cells from any mature cells in our bodies.

On the other hand, adult stem cells are more limited (multipotent), which means that they can only develop into some cell types in the body. Their main functions are to supply new cells as an organism grows and to replace damaged cells. For example, bone marrow stem cells (known medically as haematopoietic stem cells) are only able to replace the different blood cells in the body such as red and white blood cells.

A less mentioned but equally important cell type is the progenitor cells. These cells are considered similar to stem cells but have limited ability in self-replication and can only develop into one or a few specialised cell types.^[2] For instance, retinal progenitor cells can only develop into photoreceptor cells and other retinal cells but not blood or bone.

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Stem cells as a potential treatment for eye diseases

Nerve cells in our bodies do not regenerate once damaged. The retina is a structure wired with complex nerve connections to the brain which enable us to see when light is detected by the photoreceptor cells. However, the photoreceptors and the supporting retinal pigment epithelium (RPE) cells can be damaged at any age due to either genetic mutations (e.g. inherited retinal degenerations) or wear and tear changes (e.g. age-related macular degeneration/AMD), or even a combination of both. Scientists are exploring the possibility of transplanting retinal cells cultured from stem cells into eyes affected by two conditions, Stargardt disease and AMD.

In both conditions, the RPE cells are damaged which in turn causes secondary damage of the photoreceptors. To replace these cells, RPE generated from different sources including hESCs (hESC-RPE), hiPSCs (hiPSC-RPE) and adult stem cells have been transplanted into the eye in various clinical trials.

1) Pluripotent stem cells

Multiple trials have been undertaken or are currently ongoing investigating the safety of hESC-RPE transplantation. Majority of these trials are in the phase 1 or 2 stages. The scientific summaries of the reported trials are listed as follows:

• Schwartz and colleagues 2012, USA (preliminary results; NCT 01344993 and NCT 01345006)
• Schwartz and colleagues 2015, USA (report on medium to long-term follow-up results) 
• Mehat and colleagues 2018, UK (NCT 01469832)
• Da Cruz and colleagues 2018, UK (NCT 01691261)
• Kashani and colleagues 2018, USA (preliminary results; NCT 02590692)

Comparatively, clinical trials investigating human hiPSC-RPE transplantation are relatively few. The world’s first successfully transplanted iPSC-RPE was reprogrammed from skin cells of a 77-year-old woman with AMD. No major safety issues were reported at 1 year after surgery and the graft (transplanted cells) continues to survive after 4 years. However, the hiPSC-RPE from a second patient in the same trial were found to have genetic changes prior to transplantation that might alter gene function.^[3] These might have been instigated during cell reprogramming and as a result the trial was paused. Since then, scientists have moved from using self-donated iPSCs to skin cells harvested from anonymous donors which are screened thoroughly for genetic mutations prior to being deposited in a “cell bank”. Yet, the high cost of maintaining such banks precludes iPSCs from being scaled up into larger clinical trials at present.^[2]

2) Adult stem cells

Intravitreal injections (a commonly performed outpatient procedure by eye doctors) of bone marrow stem cells harvested from patients themselves have shown to be safe and potentially beneficial in a multitude of eye conditions, including inherited retinal degenerations, AMD and conditions affecting the blood circulation of the eye such as diabetic eye disease. Instead of replacing the damaged retinal cells, the bone marrow stem cells release proteins (known as neurotrophic factors) that protects the surviving retinal cells from further deterioration (neuroprotection).^[4] The reported trials (mostly phase 1 studies) are listed here:

• Siqueira and colleagues 2011, Brazil 
• Siqueira and colleagues 2013, Brazil 
• Siqueira and colleagues 2015, Brazil
• Park and colleagues 2014, USA (NCT 01736059)

3) Progenitor cells

Progenitor cells of retinal and neural (eventually becoming nerve tissues) origins are also being investigated as potential treatment for the most common form of inherited retinal degeneration, retinitis pigmentosa. Retinal progenitor cells mainly release neurotrophic factors to protect the surviving photoreceptors but it has been shown in animal models that some are able to replace lost photoreceptors.^[5] The preliminary results of current trials for retinal progenitor cells (RPCs) demonstrated that the procedures are safe with some visual benefit though the small number of patients treated precludes drawing conclusions of its effectiveness.^[6-8] The ongoing trials are listed as follows:

• Sub-retinal delivery of RPCs (phase 1/2, NCT 02464436)
• Intravitreal delivery of RPCs, jCell (phase 2, NCT 03073733)

On the other hand, neural progenitor cells (NPCs) protect the surviving photoreceptors in a slightly different manner. The group heading the ongoing clinical trial (NCT 04284293) investigating this approach has programmed the NPCs (CNS10-NPC) to develop into a type of nerve cell called glial cells, which exerts a neuroprotective effect on surrounding nerves.^[9]

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Is it safe?

The main safety concern with stem cell therapy is the risk of tumour formation. Tumour cells are basically cells that have uncontrolled growth and this is of particular concern with stem cells as they possess the unique ability of multiplying itself without any limitations. Hence, stem cells destined for transplantations are checked thoroughly prior to surgery to make sure that they only contain development markers for the cell type of interest. So far, none of the hESC-RPE and hiPSC-RPE trials have reported such occurrence, with the longest follow-up being 4 years after transplantation.^[10-13] 

Like all other organ transplant procedures using organs harvested from other individuals (known as allogenic transplant), stem cell transplants sourced from cell banks (either hESCs or hiPSCs) risk inciting an immune reaction in our bodies which could lead to graft rejection. This is because the immune system recognises the graft as foreign and will mount an attack. As a result, patients in initial trials are often put on high dose medications that suppress our immune system (called immunosuppressors) for a period of time (up to 3 months).^[11],[14] These medications have a myriad of side effects, which include increasing susceptibility to infections. Such an effect could potentially be harmful for elderly patients. However, a more recent trial conducted by Da Cruz and colleagues have demonstrated that the risk of graft rejection can be adequately controlled with shorter period of immunosuppressor intake (3 weeks) combined with steroid injections and a steroid implant inserted during surgery.^[12]

In contrast, such medications can be avoided by using our own stem cells (autologous transplant) as in the case of bone marrow stem cell transplant or iPSCs. Although RPCs are allogenic, they do not seem to cause an immune reaction when injected into the eye.^[15]

Other complications or side effects reported in hESC-RPE transplantation trials are mainly associated with the surgical procedure itself, which include worsening of cataract and a case of severe eye infection which was treated successfully with standard treatment protocols.^[10]

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Beware of unregulated “stem cell trials”

Many “stem cell trials” are listed on the clinical trials registry ClinicalTrials.gov provided by the US National Library of Medicine. However, it is important to note that presence of a study on ClinicalTrials.gov does not mean that the study has been evaluated by an ethics committee or given approval. Furthermore, clinics running some of these trials charge patients exorbitant fees to participate and tend to be euphemistically called “patient-funded research”. Therefore, if you are interested in a particular trial, we strongly advise that you seek the opinion of your doctor on whether they think it is reputable and ethically approved.

One notable example is a “trial” in the US where multiple patients were injected with autologous adipose (fat) tissue-derived stem cells (NCT 02024269—now withdrawn) which resulted in severe visual loss in both eyes of 3 patients.^[16] All 3 patients paid $5000 for participating in the “trial” which had supposedly obtained approval from the US Food and Drug Agency (FDA) but this was not stated in the provided patient information leaflets.

Another example is the ongoing Stem Cell Ophthalmology Treatment Study (SCOTS and SCOTS2) for multiple eye conditions. There are no indications that both trials are approved or reviewed by an ethics committee and patients were reportedly charged $20,000 for the treatment.^[6] Publications associated with these trials tend to be small case reports (only a small number of patients reported) with follow-up duration ranging from 6-15 months. Most patients reported by the principal investigator of these trials obtain visual improvement with no serious complications.^[17-19] However, other groups not associated with the SCOTS or SCOTS2 trials have reported serious complications such as recurrent retinal detachment and formation of epiretinal membranes (a sheet of cells developing on or above the macula) which can lead to visual deterioration.^[20],[21]

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Limitations

Although we have made significant strides in stem cell technology over the last two decades, stem cell therapy for genetic eye conditions still has some ways to go before reaching the bedside as a treatment option. The main challenge facing scientists now is that current stem cell-derived retinal photoreceptor cells are still not fully mature and functional, and therefore having difficulties to replicate or replace the lost cells. The transplanted cells will also need to integrate seamlessly with the other surviving photoreceptors to have a therapeutic effect. Once these issues are solved, we may be one step closer to using cell therapy to treat previously incurable eye conditions.

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References

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