Cell Replacement Therapy: A Promising but Unproven Approach to Repairing the Parkinson's Brain
What is cell replacement therapy and how do doctors believe it may one day help people with Parkinson's disease?
Cell replacement therapy seeks to restore function in the body by replacing cells lost due to disease with new, healthy ones. In Parkinson's disease, this means replacing dopamine cells in the brain, the main type of cell that degenerates in the disease. Researchers hope that one day they will be able to use stem cells or iPS cells to successfully engineer healthy new dopamine-producing cells. These healthy cells would then be implanted into the brain, where the cells could in theory restart the brain's production of dopamine and restore normal movement.
What scientific challenges stand in the way of making this happen?
At this time scientists are working to overcome two major challenges: first, engineering the dopamine-producing cells (see Stem Cells 101); second, getting these cells to function properly once they are transplanted into the brain. To date, scientists have had the most success generating robust dopamine neurons, in both quantity and quality, using embryonic stem (ES) cells. However, whether these engineered dopamine neurons are sufficiently 'authentic' — that is, whether they express everything natural ones do — is a remaining challenge.
Even if seemingly authentic dopamine neurons can be generated, researchers face an enormous hurdle in coaxing these cells to grow and make the correct connections in a host brain. This involves determining where to place the cell grafts and how to deliver them without causing additional brain damage or triggering immune rejection or inflammatory effects.
Additionally, the new cells must also be able to retain the characteristics of a dopamine neuron once implanted in the brain, where they will be exposed to other factors that may influence their further development and survival. Following transplantation into pre-clinical models, today's engineered cells often do not survive for long, can turn into different cell types or in some cases cause uncontrolled cell growth. For this reason, they are obviously not yet ready for therapeutic use in humans.
Initial attempts in the 1990s to transplant fetal brain tissue — which contains immature dopamine cells — into people with PD revealed some of these challenges. Although the strategy provided benefit to some people, it left others with severe complications, including 'off-medication dyskinesias'. (Fetal tissue transplant studies have been considered to be a first step 'proof of concept' for moving into stem cell trials, as the limited availability of fetal tissue may make it infeasible as a widespread treatment option regardless of therapeutic promise.)
In 2008, reports from several research groups pointed to a potentially new challenge. Although fetal tissue transplants can survive in the brains of people with Parkinson's for many years, in some people whose transplants were examined after they died, scientists saw clear signs of PD-like pathology even in the transplanted tissue.
In September 2008, MJFF convened top experts on cell replacement therapy in PD for a summit meeting to discuss these findings. Outcomes from the meeting pointed to an uncertainty about whether PD pathology adversely affected the transplants in the few cases that scientists could study. But the finding did raise the discomfiting possibility that even transplanted healthy tissue might eventually succumb to the disease processes of Parkinson's. If true, the pathology issues seen in fetal tissue transplants could also occur in stem cell-derived transplants.
Understanding more clearly how transplanted tissues, either fetal or stem cell-derived, respond within a host brain affected by Parkinson's disease is essential before widespread therapeutic cell replacement can be delivered to people. MJFF has funded some studies in this area, including a 2008 Rapid Response Innovation Award aimed at replicating in mouse models the findings from the fetal tissue transplants. We hope to identify the mechanisms that allow the disease to transfer between cells to better understand how PD arises and progresses, and to develop new therapies that can slow disease progression (something no currently available treatment has been proven to do).
What is The Michael J. Fox Foundation's view on cell replacement therapy?
Based on evidence to date, the Foundation believes that the development of viable and feasible cell replacement therapies could revolutionize the treatment of Parkinson's disease. However, the hurdles to success are great; much work remains to be done before cell replacement therapy for PD is a viable therapy for patients. Furthermore, even if all roadblocks are overcome, cell replacement therapy may not be the “silver bullet” for treating PD. For example, researchers feel that dopamine cell replacement might have little or no effect on symptoms of PD not directly related to loss of dopamine cells, such as cognitive dysfunction, sleep problems, depression, constipation and gait and posture problems.
Cell replacement therapy is one of a number of potentially promising therapeutic approaches that could protect or restore function in people with PD, and MJFF is leading efforts in a variety of these areas. As part of our portfolio of potential therapeutic targets, we will continue to monitor cell replacement developments for opportunities where the Foundation can help in advancing this research.
For more information on MJFF investments in cell replacement therapy research, please search our Searchable Database of Funded Grants.
September 2009
