No area of medicine in recent years has produced as much hype and hopeful thinking than that of stem cells. So much so that two US presidents have issued executive orders to control their use in research (EO:13435, EO:13505). Many countries continue to heavily regulate or even ban their use outright.
In this article, I will attempt to cut past the ethical dilemma surrounding stem cell use and focus on the hard science.
There are a number of neurological disorders that are fundamentally caused by a loss of neurons, supporting cells or damage to particular circuits deep within the brain.
On a theoretical level, all of these problems could be solved using stem cells. A tantalising thought.
The logic of the situation is enticingly simple: find which cells/ cell groups are damaged, use stem cells to produce replacement cells and transplant them into the correct area, undoing the damage.
Presto, neurodegeneration solved. As beautifully simple as the thought of this is, it shouldn’t surprise you to hear that it is, in fact, a mammoth task, currently being undertaken by thousands of researchers all over the world. We have had a massive growth in knowledge, but to date this has provided limited progress in clinical application.
One of the major issues facing stem cell treatment is the relative complexity of each neurodegenerative disease. For example, in multiple sclerosis (MS), you would expect to find multiple lesions in different areas of the central nervous system (CNS), with no obvious correlation of the location of these lesions between patients. This provides a predicament when designing stem cell transplant treatments. Different areas of the brain that contain different circuitry, unique to each and every patient.
On the other hand, Parkinson’s disease (PD) is fairly simple: one area of one structure loses one type of neuron.
In this case, the circuitry is well mapped and is usually fairly homogenous between patients. Therefore, PD is seen as much more favourable starting point for the first stem cell transplantations.
Sadly, the complications don’t stop there. After gathering the required cells, we need to find methods for introducing these cells into the area of the brain where they are required, encourage them to grow and thrive, re-integrate the broken and lost circuitry and restore function over the long term. Potential stem cell transplant therapy can fail at any one of these monumental hurdles.
Replacing the lost cells
Parkinson’s disease is characterised by the loss of A9 dopaminergic neurons from the substantia nigra pars compacta of the midbrain. One of the first stem cell studies in PD used embryonic stem cells (ESCs) to create dopaminergic neurons, these cells were subsequently transplanted into an animal model. The cells successfully integrated into the pathological circuitry and did not have uncontrolled or abnormal growth, with some motor improvement. A following study used foetal stem cells in human PD patients. The cells successfully survived, reintegrated the circuitry and even reduced motor symptoms. The patients from this trial have been followed up for 18 and 15 years respectively and maintain reduced motor symptoms post transplantation to date.
Induced pluripotent stem cells (iPSCs) have also been successfully transplanted into a non-human primate model of PD. In this case, the cells survived, re-integrated the circuitry and did not require immunosuppression. The motor symptoms were also observed to improve after transplantation. This was a very strong proof of concept for the use of iPSCs in future treatment of PD. The first iPSC transplant trials in PD are due to take place within the next few years.
Managing inflammatory mechanisms
Despite the initial negative outlook for the use of stem cells in MS, preliminary studies yielded interesting results. As the damage in MS is an inflammation-driven process, the microenvironment would lead to the destruction of any transplanted cells over time. The dispersed nature of the lesions also poses a problem. However, one study in mice injected neural stem cells into the systemic circulation.
The cells not only migrated to each of the lesions, they differentiated into the required oligodendrocytes and remyelinated axons. A follow up study using similar stem cells also showed a suppressive effect on inflammatory mechanisms.
Another direction being explored in MS is the use of autologous haematopoietic stem cell transplants (AHSCT). In MS, the lesions are caused by the immune system attacking the CNS. The aim of AHSCT is to reset the immune system. Although this treatment is well established for certain cancers like myeloma, use for MS is still under investigation. Some patients in trials have reported a decrease in relapses and symptoms, whilst others did not respond to the treatment. A 5-year follow-up study reported long-lasting suppression of inflammation and a decrease in the rate of brain atrophy. This treatment is currently in Phase II clinical trials.
Supporting diseased neurons
Amyotrophic lateral sclerosis (ALS) is a degenerative disease of motor neurons. There is currently no disease modifying treatment available for sufferers and understanding of the pathology is still very limited. Stem cells have successfully been used to produce motor neurons in vitro that show similarities to their in vivo counterparts.
However, the major drawback of using stem cells in ALS is the projection range of the lost neurons. Motor neurons have very long axons and innervate targets up to a meter away; replacing the neurons where they are lost will have no effect if the projection fibre isn’t replaced. Therefore, the aim of stem cell transplantation will be to add cells that can produce supportive factors such as BDNF and NGF to support the in situ diseased motor neurons.
A phase 1 clinical study assessing the feasibility and safety of MSC transplantation has been undertaken in humans. MSCs were transplanted directly into the spinal cord, no post-transplant toxicity or tumours were observed showing that this is a potential safe intervention. The next phase of this study will be to investigate whether these BDNF secreting MSCs provide an efficacious treatment for ALS.
Increasing the survival of medium spiny neurons
Huntington’s disease is caused by a genetic mutation on chromosome 4, resulting in a polyglutamine repeat in the huntingtin protein. Neurologically, this results in the death of medium spiny neurons in areas of the brain including the striatum. Similarly to ALS, stem cell transplantation in HD is aimed at altering the microenvironment for the diseased cells to maximise their chances of survival.
This can be done by secretion of various growth factors such as BDNF, GDNF, NGF etc. Initial studies in mice utilizing genetically modified MSCs to overproduce BDNF have shown increase in neurogenesis, decreased behavioural anxiety and an increase in life span. This research is very recent, but hopefully within a few years safety trials can begin in human patients.
Saving the Retinal Pigment Epithelium
Macular degeneration (MD) causes blindness by destroying the retinal pigment epithelium (RPE). The RPE is the support structure for the cone photoreceptors responsible for the central part of your visual field. The advantage of researching stem cell treatments on the retina is that you can do controlled trials on one patient, by using a stem cell treatment on one eye, and comparing it to the other. The eye is also a well-contained structure, so any intervention by transplanting cells is unlikely to migrate to the rest of the body.
The first human transplant of ESCs was used to treat MD. The ESCs were forced to differentiate into RPE tissue, this tissue was then transplanted onto the retina of MD sufferers. The study showed that the transplant was not rejected, did not undergo uncontrolled proliferation or abnormal growth. There was no significant gain in vision post transplantation but this study was mainly assessing safety and proof-of-concept. Follow up studies are aiming to treat individuals where the disease is less advanced and the researchers are hoping that visual loss can be mitigated or even reversed.
The first human clinical trial using iPSCs was undertaken on patients suffering from macular degeneration in September 2014 but was stopped early in 2015 due to a genomic instability in the cell line. The trial subsequently resumed months later with initial results expected in 2017.
Fixing the poisonous microenvironment
Alzheimer’s disease also poses a seemingly insurmountable challenge to stem cell researchers. The damaged neural circuitry is dispersed throughout most of the brain, including the basal systems and the cortex. Producing replacement cells for these areas is theoretically possible, however adding a number of neurons to fix aberrant circuitry doesn’t work when there is no circuitry left to patch. The damage in Alzheimer’s disease is usually so extensive that the microenvironment is completely inhospitable to transplanted neurons.
Needless to say, progress in this area is limited with current trials focussing on transplanting cells that produce nerve growth factor (NGF) as a method of fixing the poisonous microenvironment. The aim of this is to slow down the death of the in situ neurons with the ambition of slowing down the disease. Following on from this study, another group used brain derived neurotrophic factor (BDNF) secreting stem cells in a transgenic mouse model. Optimistically, this group found that spatial learning and memory deficits were rescued post transplantation and hippocampal synaptic density increased. Interestingly, the levels of A-beta plaques and abnormal tau protein aggregations were unchanged, calling into question our understanding of the underlying pathology.
There is no doubt that the basic science research into stem cells has made huge leaps forwards in recent years. However, there has been a distinct lack of translational medicine emerging from this. Hopefully, the potential treatments are on the distant horizon, and in recent years a number of Phase I + II trials have started to be undertaken. Although it is too early to speculate on the results, it is no doubt an exciting time in stem cell research. If successful, these treatments could offer a glimmer of hope to patients suffering the diseases that, to the date, have no treatment.