Evaluating the Potential of Stem Cells: A Critical Assessment
ASENT 5th Annual Meeting
Thursday, March 13 - Saturday, March 15, 2003
Capital Hilton Hotel, Washington, DC
Speaker Abstracts: Evaluating the Potential of Stem Cells: A Critical Assessment
What Has Fetal Transplantation Taught Us About Cellular Transplantation Into The CNS?
Olle Lindvall, MD PhD
The clinical trials with transplantation of brain tissue from aborted human fetuses in patients with Parkinson’s disease (PD) and to some extent also in patients with Huntington’s disease provide proof-of-principle for the cell replacement strategy in the human brain. In PD, for which clinical cell therapy research has reached the furthest, intrastriatal grafts of mesencephalic tissue can reinnervate the striatum, restore dopamine release and movement-related frontal cortical activation, and give rise to significant clinical improvement. However, it is unlikely that transplantation of human fetal tissue can be developed into therapies for large numbers of patients due to poor availability of tissue for grafting and problems with standardization, purity and viability. Stem cells of different sources could be useful to generate almost unlimited numbers of specific neuron types, e.g., dopamine neurons for PD. Most importantly, the clinical trials as well as studies in animal models have taught us which requirements have to be fulfilled in order for a graft to induce marked and clinically valuable improvement in patients with PD: (1) The grafted cells have to express the complete cellular machinery for DA synthesis and release, and possess the properties of fully mature mesencephalic DA neurons, both morphologically and electrophysiologically. (2) At least 100.000 grafted DA neurons should survive long-term in each putamen; (3) The grafted DA neurons should re-establish a dense, functional, DA-releasing terminal network in large parts of the striatum; (4) The grafts have to become functionally integrated into host basal ganglia-thalamo-cortical circuitries; (5) When tested preclinically in animal models of PD, the cells must be able to reverse functional deficits resembling the symptoms in patients. Thus, the biological problems which have to be solved in order to develop stem-cell based therapies for brain diseases are complex and should not be underestimated.
The Biology of Neural and Non-Neural Stem Cells
Clive Svendsen, PhD
What is a stem cell? This is becoming more than a semantic issue in biology these days, as cell therapy approaches clinical trials. It is vital to know exactly what is going on during the growth of “stem cells” in the culture dish, and how pure the population actually is. Which is the best source for generating stem cells – the blastocyst, fetus or adult? Can they all be grown forever in the tissue culture dish – or do they change with time? Are neural stem cells generated from these tissues really the same? Clearly the old adage “rubbish in/rubbish out” is well applied to cellular therapy. To avoid catastrophic clinical outcomes, cells must be characterized to the best of our abilities. In this presentation, the biology of “stem cells” generated from different species and different tissues will be presented. One underlying theme will be that in many cases “stem cells” are not actually being grown in culture, but instead more restricted “progenitor” cells – with a fixed genetic background related to their origin. Another is that human and rodent progenitor cells are dramatically different in both growth characteristics and phenotypic potential. Finally, “stem cells” generated from adult human tissues do not overlap seamlessly with those from embryonic sources. These differences appear to be the rule, while the rare exceptions (where cells can return to a primitive state or “trans-differentiate” between germ layers) often grab the spotlight.
The Therapeutic Potential of Stem Cells for Nervous System Diseases
Ole Isacson, Dr. Med. Sci.
The mammalian adult brain is a regenerative system capable of incorporating embryonic stem (ES), progenitor or fetal primary neurons into new circuitries. These implanted or regenerating neurons and glia grow to functionally repair damaged or degenerated neuronal connections. First, by transplanting immature neurons into various locations in the brain of animal models we determined which connections and reparative interactions with the host are possible using fetal or ES cells. We found that implanted fetal or ES cells derived dopamine neurons can survive long-term and gradually reduce signs of Parkinson’s disease (PD) in various animal model systems. Second, the differentiation pathways and molecular switches necessary for specific DA cell identity and growth have been evaluated. There are genetic modifications and trophic factor support involving Nurr 1, PitX 3, Shh, FGF8 and markers modifying growth cone behaviors and cell type specification from ES to dopamine neurons. The presence of these factors can further enhance the restoration of normal neuronal dopamine function. The functional studies of neurodegenerative models and potential repair in Parkinson’s, Huntington’s disease and amyotrophic lateral sclerosis (ALS) provide new opportunities for evaluating the therapeutic use of stem cells.
Development of Neural Stem Cells for Treatment of Neurological Diseases
Karl K. Johe, PhD
Human neural stem cells can be effectively isolated, expanded, differentiated in vitro, and therefore characterized during development as a drug. However, depending upon the expansion capacity of individual stem cell lines and their differentiation potentials in vivo as well as the targeted indication, strategy for developing a stem cell based drug development can vary widely. We have isolated, expanded, and characterized neural stem cells from several regions of human fetal CNS. Some of these can be expanded up to about 60 cell doublings, which represents near the mammalian senescence point and enough cells to treat all current and future patients for certain indications. Others can be expanded for only up to about 20 cell doublings, which means having to recruit new cell lines periodically and to re-test each preparation. Such differences in the cells’ expansion capacity as well as differentiation capacity seem to roughly correlate with in vivo neurogenesis during CNS development. We are testing these cell lines in various animal models of neurological diseases.
Stem Cells: Regulatory Challenges and Initiatives
Phillip Noguchi, MD
A simple definition of a stem cell is a cell that can regenerate itself and can also produce a more differentiated cell. This definition suggests the potential for limitless bounty of source material, unlike say fetal cell transplants, as well as the potential to create specific neurological cell types that might be better matched to specific patient deficits. As with any new approach to treatment of diseases, however, the transformation of potential into reality is developed through a careful process of controlled clinical trials with the best refined clinical end points, rigorous development of the product based on the most stringent scientific data, and patience. For example, the very limitless regenerative potential of a stem cell raises concerns over possible development of a malignant cell phenotype. For implantation into the CNS, even a ‘benign’ slow growth can be deadly. Creating a differentiated cell phenotype with 95 % ‘purity’ is not nearly ‘good enough’, if the remaining 5 percent are of a different phenotype. We know that stem cells whatever the state of differentiation can migrate throughout the body. It would be scant comfort to be able to treat end stage Parkinson’s disease, if some of those differentiated cells migrated to the A-V node of the heart, and caused uncontrolled arrhythmias. CBER has initiated a number of ventures to augment the science based needed for clinical trials for stem cells. CBER and NINDS have signed a memorandum of understanding (MOU) whereby FDA reviews serve as liaisons to help formulate funding initiatives that will lead to research in areas of FDA concern; NINDS scientists are attending early FDA meetings with sponsors to learn about the FDA regulatory role in product development. NIA and CBER are collaborating in examining human stem cells with micro arrays to determine reproducible markers of differentiation that might be useful for stem cell product characterization.