Parkinson’s Disease is a neurodegenerative motor disorder, caused by the progressive degeneration of dopaminergic neurons in the brain. Current treatments only alleviate the symptoms of the disease rather than target the root cause, so they are far from adequate. A cure would require repair of the brain itself. Given that the incidence of this age-related condition is set to escalate with the aging population, it is essential that novel therapies that can at least slow or halt progression of the disease are developed.
Once such approach is to replace the brain cells that have degenerated, by degtransplanting healthy stem cells into the brain. Researchers at the University of Wisconsin have recently discovered that embryonic stem cell-derived healthy neurons are able to integrate into damaged circuits in the brain and restore motor function. Although this is a proof of concept study, it represents yet another encouraging step towards the use of stem cell therapy to treat Parkinson’s patients in the clinic.
Indeed, several trials have now provided ‘proof-of-principle’ for this approach, showing that cells taken from the healthy, developing brain can successfully integrate and function after transplantation into the patients’ brains. However, one major limitation to this approach is the poor survival of the transplanted neurons, with only about 5 per cent surviving implantation. This may be due in part to rejection of the cells by the patient’s immune system.
Researchers in the Dowd laboratory at NUI Galway are exploring the use of biomaterials – materials that have been specifically engineered to interact with living systems for therapeutic purposes – to address this limitation, aiming to enhance the repair provided by stem cell-based therapies. Biomaterials, such as collagen and fibrin, can be used as scaffolds to offer a supportive matrix for transplanted stem cells, and can also be used for delivery of other molecules that can enhance the survival of brain cells.
Transplantation is not the only context in which stem cells are useful in the battle against this disease. Researchers are also using them to uncover what exactly is going awry in these patient’s neurons, by taking a sample of their cells and reprogramming them to become neurons in the lab, in order to examine how they are behaving differently to healthy neurons. Using neurons derived from human patients is far more relevant for studying disease than looking at them in a mouse model. The Kunath group here in Edinburgh is making use of this approach to try and understand genetic forms of Parkinson’s Disease.
Stem cell-derived neurons grown in the lab can also be used as a platform to study how effective a drug is at restoring dopaminergic neurons. There are two types of stem cells that can be used for this approach: embryonic and induced pluripotent. Stem cells have traditionally been obtained from embryos and aside from some ethical concerns, issues can also arise when these stem cells are used for drug screens. Embryonic stem cells are taken from a very different environment to the typical adult brain and so neurons derived from these will not necessarily respond the same way as neurons from a Parkinson’s, or for that matter any, adult brain. Parkinson’s patients tend to be older, so their brain cells exist in an aged and diseased environment, in contrast to the young, healthy and still developing environment of the embryonic brain. This means that occasionally drugs found to be effective in embryonic stem cell-derived cultures prove to be ineffective in the clinical setting. Induced pluripotent stem cell-derived neurons, isolated from patients’ adult skin cells, therefore represent a valuable tool for performing screens, allowing for testing of a drug’s efficacy in patients with a variety of disease severities and drug metabolism responses.
Key challenges to be addressed going forward include figuring out how to grow stem cell-derived neurons efficiently and in sufficient quantities, and ensuring their adequate survival following transplantation. There have also been reports that stem cell-derived neurons transplanted into Parkinson’s brain can later develop abnormal clumps called ‘Lewy bodies’, a key hallmark of Parkinson’s pathology. This further supports the theory that the brain microenvironment and inflammation may be contributing to the development of disease.
So, while stem cell therapies certainly represent a very promising option, studies investigating the underlying causes of Parkinson’s remain a very important piece in the puzzle and will help to ensure their success in treating the disease in the clinic.
Written by Niamh McNamara and edited by Ailie McWhinnie.
Niamh’s thoughts… Human clinical trials examining the safety and efficacy of stem cell transplants in Parkinson’s patients are now ongoing. While I have highlighted some of the challenges remaining in this field and how stem cell-based therapies alone will not likely cure the disease, their significant potential for combination therapies, such as gene-modification approaches or co-delivery with drugs that could provide neuroprotective factors to help the neurons survive and thrive, means the possibility of a cure could be on the horizon.