Cell Replacement Therapy: Restoring Function by Replacing Dead and Diseased Cells with Healthy Ones
What is cell replacement therapy?
The basic principle of cell replacement therapy for central nervous system (CNS) disorders is quite simple: restoration of function lost through damage or disease in the CNS by the replacement of dead cells with new healthy ones. Given the complexity of both the structure and function of human brain and spinal cord, this prospect may seem remote. In fact, until 25 years ago, the possibility of using cell replacement for CNS repair was regarded as science fiction. Today, cell replacement therapy is a realistic therapeutic possibility. Extensive animal experimental studies performed over the last two decades have shown that neuronal replacement and partial reconstruction of neuronal circuitry is indeed feasible. If this approach can be made to work in the human nervous system, cell therapy could provide radical new treatments for severe neurological disorders.
Because the loss of dopamine-producing cells is the hallmark of Parkinson's disease pathology, cell replacement therapy for Parkinson's aims to replace diseased or dead dopamine-producing cells with new cells. The cells affected by PD are found within a region of the brain called the substantia nigra, which connects to the striatum, a separate region involved in regulating movement. Researchers theorize that new cells can be placed in the striatum to provide a replacement source of dopamine or, alternatively, in the substantia nigra, where they could potentially reconstruct the natural brain dopamine production process (which some researchers believe would provide a more beneficial outcome).
Cell replacement therapy is conceptually different from other cell-based efforts that aim to improve the function of an individual's remaining dopamine cells or to prevent further loss of these cells. These efforts seek to inject or implant cells that expose remaining dopamine cells to growth factors or other survival-promoting molecules, but do not necessarily replace lost cells. (For more information on such efforts, please see the Foundation's position paper on Trophic Factors.)
Replacement cells can come from a variety of sources:
- Dopamine neurons obtained directly from fetal brain tissue
- Dopamine neurons derived from human embryonic stem cells
- Dopamine neurons derived from neural stem cells in fetal or adult brain tissue
- Dopamine neurons derived from other stem cell sources (e.g. bone marrow, umbilical cord, amniotic fluid)
In addition, some researchers are looking into the possibility of generating new dopamine neurons from the diseased/injured adult brain itself through self-repair mechanisms. Often referred to as 'endogenous' stem cells, this source of replacement cells as a realistic treatment remains hypothetical at this stage.
A promising source of replacement dopamine neurons (and the only source that has been tested in approved clinical trials) is fetal brain tissue. But due to difficulties obtaining such tissue and the currently inconclusive results from initial trials, much work has focused on generating new cells from various stem cell sources.
Why is cell replacement therapy important?
Cell replacement therapy has inspired a significant amount of interest and hope among both doctors and patients in the PD community because it theoretically holds potential to replace lost dopamine neurons, effectively repairing the brain and halting the disease - something no currently available treatment can do.
Does it matter which kind of stem cells scientists work with?
Based on research results to date (including projects funded by MJFF — see Unlimited Numbers of Purified Midbrain Dopamine Neurons from Human Embryonic Stem Cells and Identification of Novel Determinants for Dopamine Neuron Generation in Vivo & Embryonic Stem Cells), Parkinson's scientists have had greater success manufacturing dopamine neurons from embryonic stem cells than from other stem cell sources. While research undertaken using adult stem cells has yielded dopamine neurons, the resulting neurons have not been as robust in quantity or in quality as those generated using embryonic stem cells.
The reasons for this are not fully understood; researchers theorize, however, that it is at least partly because embryonic stem cells are undifferentiated, or "pluripotent." This means that they are still at a stage of development in which they have the potential to become any type of body cell. Adult and umbilical cord blood stem cells, on the other hand, have already undergone certain processes placing restrictions on their destinies.
What stands in the way of cell replacement therapy for Parkinson's?
Scientific issues. Scientists have struggled to create 'authentic' dopamine neurons - that is, neurons that can do and express everything natural ones can - from various stem cell sources. Although we are getting closer, important details of what makes up a true dopamine neuron remain unknown. Another problem is that even when researchers have obtained seemingly authentic dopamine cells, little success has been achieved in coaxing these cells to incorporate into host animal brains without dying, turning into a different cell type or, in some cases, causing uncontrollable cell growth. (The Foundation's Cell Line II initiative was designed to further research toward successful transplantation into a host brain.) And in the early attempts at grafting fetal tissue into human patients, severe clinical complications arose in some cases, including off-medication dyskinesias. Overcoming these problems is essential before work can go forward.
Surgical issues. Researchers face an enormous challenge in getting grafted cells to grow and make the correct connections in the brain, which involves determining where to place the cell grafts and how. Another major issue is optimizing delivery of cells to a host brain without causing additional brain damage.
Manufacturing and regulatory issues. Responsible and well-regulated manufacturing procedures (termed GMP for "Good Manufacturing Procedures") must be developed and enforced to ensure that clinical-grade stem cells can be produced in sufficient quantities for widespread 'off-the-shelf' use in patients. Additionally, regulation is required to reassure patients and health care providers that manufactured cells will reliably and safely meet their needs without danger of being tainted by non-human animal contaminants.
Ethical/political issues. Polling information indicates that some people believe an embryo has the moral status of a person from the moment of conception, and that any activity that would destroy it - even medical research with potential to improve millions of lives - is wrong. Others disagree that the respect due an embryo should equal that given to a fully formed human, and consider it immoral not to use embryos that would otherwise be destroyed to develop potential cures for disease affecting millions of people. An additional concern related to public policy is whether NIH grants to academic institutions should be used for research that some Americans find unethical.
Other issues. Even if all of the above roadblocks were overcome, problems will remain to be solved. For example, researchers hypothesize that dopamine cell replacement would have little or no effect on the dopamine-non-responsive symptoms of PD, which many patients report to be among Parkinson's most disabling aspects.
What attempts have been made using cell replacement therapy in PD patients?
In the past 10 years, several clinical trials involving human fetal tissue transplants have been conducted. The results demonstrated a wide variability in patient response, and some patients experienced adverse side effects including off-medication dyskinesias. These results prompted calls to halt future trials. In a 2001 editorial, the journal Nature Medicine cautioned: "Most clinical and basic scientists involved in neural transplantation agree that the field is in its infancy and that optimal methods of tissue preparation and implantation are not yet established. The optimal surgical approach also has not been worked out and surgeons differ widely in what they consider to be the best approach."
In addition to the work in fetal tissue trials, in recent years claims and reports have surfaced of some clinics offering stem cell therapies for PD patients. In some cases, this may involve direct injection into the blood stream of cells derived from bone marrow and umbilical cord blood, while in other cases direct grafting of stems cells to the brain may be offered. Although bone marrow/umbilical cord blood approaches have shown promise in treating some blood-based diseases (such as leukemia), it should be noted that no approved or accepted human trials using either of these methods have been published for PD. Such treatments are often expensive and may be risky, and it is unclear whether they provide any meaningful benefit for PD patients. Individuals interested in pursuing such treatments should carefully discuss this with their physician.
What is The Michael J. Fox Foundation's view on cell replacement therapy?
Based on evidence available to date, the Foundation believes that the development of viable and feasible cell replacement therapies could revolutionize the treatment of Parkinson's disease. Nonetheless, the scientific, engineering, manufacturing and ethical hurdles necessary to achieve success with cell replacement therapies are great, and much work remains to be done before cell replacement therapy for PD is a viable therapy for patients.
For more information on MJFF investments in cell replacement therapy research, please search our Funded Studies Database.
NOTE: The first paragraph of this paper was adapted from Cell Replacement Therapy: Helping the Brain to Repair Itself (October 2004), with permission from its authors, MJFF Scientific Advisory Board members Anders Björklund, MD, PhD, and Olle Lindvall, MD, PhD.
April 12, 2007
