A short history of cell replacement therapies for Parkinson’s
Original article: Cell-based therapy for Parkinson’s disease: A journey through decades toward the light side of the Force, European Journal of Neuroscience: August, 2018.
This review piece charts the history of cell replacement therapies, paralleling the framework of the Star Wars storyline.
Why is it important?
The piece is inspired by the Star Wars themed talk delivered by Tom Isaacs, PD advocate and one of the founders of The Cure Parkinson’s Trust, at the World Parkinson Congress in Portland, OR, USA, September 2016. While impossible to capture the spirit of this informative piece, this summary captures the main factual points. Hope and progress are on the horizon.
The release of the Star Wars trilogy in 1977 coincided with major events in the field of neuroscience regarding our understanding of the brain’s ability for regeneration. It was during this time that the first preclinical experiments were carried out, demonstrating that fetal neuron precursors could survive and function when transplanted into the rodent brain and specifically when this had damage similar to that caused by Parkinson’s. These successes prompted the first two cell transplants in people with Parkinson’s in Sweden in 1987, followed by another two in 1989. The improvements seen in the last two patients launched a larger transplantation study in 14 more people with Parkinson’s in Sweden, and spurred on trials in other parts of the world, namely the US.
Thanks to the lift on the ban of federal funding for research using fetal tissue in 1993, two trials were run by the National Institutes of Health (NIH). These were designed in a different way to the original Swedish trials, including in the way that immunosuppression was carried out and the tissue itself handled. Unfortunately, the outcomes of these trials were not overall positive: even though a subset of younger patients, responsive to levodopa with less pronounced symptoms showed remarkable improvements, overall the results were negative. Additionally, the emergence of severe dyskinesias in a significant number of patients was problematic enough for many to conclude that this line of therapeutic investigation had failed.
However, closely examining these trials, and identifying areas of improvement, led experts to believe a new trial should be launched. This was TRANSEURO . The protocol was substantially improved and targeted a more specific group of people with Parkinson’s deemed likely to benefit. Eleven patients received transplants: the first procedure was performed in Cambridge, UK in May 2015 and the last in Lund, Sweden in March 2018.
Another major breakthrough was to change the pace dramatically: human embryonic stem cells (hESCs) and developments in protocols that differentiate them into dopamine neurons. With clinical trials on the verge of beginning however, a parallel problem has arisen: that of unproven stem cell therapies, available at a cost of $10,000-$30,000, which use ineffective cells and expose vulnerable people to dangerous treatments. This was a war in which Tom Isaacs was very active and remains an important issue for the Parkinson’s community.
The authors dub cellular reprogramming as “the last Jedi”: this work, which began in the 1960s, recently showed that a skin cell taken from an individual can be grown into an induced pluripotent stem cell (iPSC) which will give rise to a viable dopaminergic precursor. Moving beyond these, we now also know that cells do not need to go through a pluripotent stage: instead, they can be directly reprogrammed into a neuron (induced neurons, iNs). So tissue from an individual patient can be used to generate their specific, immunologically compatible neurons to be transplanted into their brain without the need for immunosuppression or the danger of tumour development.
Developments in recent years have moved us much closer to te viable, safe, larger scale cell therapies to be trialled for their disease modifying potential in Parkinson’s. In the words of the authors: “only time will tell the outcome, but we dare to predict that the Force will be with us.”
Original article: Cell-based therapy for Parkinson’s disease: A journey through decades toward the light side of the Force, European Journal of Neuroscience: August, 2018. Parmar, M., Torper, O., & Drouin-Ouellet, J.