Senate Commerce Subcommittee on Science, Technology, and Space
July 14, 2004
My name is Michel Lévesque, and I am a physician, neuroscientist and neurosurgeon based at Cedars-Sinai Medical Center in Los Angeles. I am Associate Clinical Professor of Neurosurgery at the UCLA School of Medicine and member of the UCLA Brain Research Institute. I am also the founder of NeuroGeneration, a biotechnology company pioneering autologous neural stem cell therapies, and Chairman of the Foundation for Neural Repair, a not-for-profit foundation, sponsoring translational research to accelerate human trials using neural stem cells.
Mr. Chairman and members of the Subcommittee, I want to thank you for the opportunity to testify today on our current experience with the use of stem cells in humans, and more specifically, adult neural stem cell-derived neurons, for neurodegenerative disorders like Parkinson's disease.
Although non-partisan, my testimony attempts to provide a realistic perspective on the promises and limitations of cell therapy for neurological disorders, either from embryonic- or adult-derived stem cells.
As a scientist and physician treating patients with irreversible neurological disorders, it is of utmost importance to understand both the fact and fiction of cell therapy and the hopes it generates in our patients and their families.
WHAT IS STEM CELL THERAPY?
Stem cell research and therapy are some of several new tools, like vaccines, genes or small molecules, targeting diseases not treated by traditional medication therapies.
Stem cell research looks at basic mechanisms of the cell cycle, at sequential expression of different genes during the formation of the embryo, and at cellular specialization and differentiation into different tissues. Stem cell research can also explore the causes of diseases, cell degeneration and cell death.
Stem cell therapy attempts to replace the cell loss and induce repair mechanisms in models of disease. Clinical research and therapeutic trials, on the other hand, study the safety and efficacy of stem cell therapy in patients with certain disorders.
Neural repair and neural transplantation using cell therapy aim at introducing cellular products, or biological modifiers, to replace the deficient cells and/or induce local neural repair in the central nervous system.
WHAT ARE HUMAN ADULT NEURAL STEM CELLS?
In nature, neural stem cells are formed after a cascade of sequential events activates genes within embryonic cells during development. They are derived from a specific layer of the embryo and can only become, under normal conditions, precursors of cells found only in the central nervous system.
Since 1996, our laboratories have been involved with the isolation and characterization of human adult-derived neural stem cells, obtained from patients undergoing neurosurgical procedures. In the adult brain, these cells cannot on their own trigger repair responses. However, if placed in experimental laboratory conditions stimulating certain genes, these neural stem cells can be "awakened" and begin to divide and replicate events of normal development.
These newly created neural stem cells can grow for several months in laboratory conditions reaching several millions in number, a process called cell expansion. Their ability to self-replicate and form all types of cells found in the central nervous system can be verified in vitro under controlled conditions. They can be placed in storage or maintained in sterile incubators until ready for use.
Prior to transplantation, neural stem cells are then exposed to a modified environment triggering differentiation, stopping the replication process to produce mature neurons of different types, including dopamine-secreting neurons, which are deficient in Parkinson's disease. In the laboratory, differentiated neurons can be characterized with specific markers, and their function demonstrated by the increased production of dopamine.
These cells have survived transplantation and corrected motor deficits in a rat model of Parkinson's disease. Our animal studies showed that human adult neural stem cells do not divide once differentiated, do not form aberrant tissue or tumors after chronic transplantation, and have normal karyotypes (number of chromosomes). Sterility is documented throughout the expansion phases.
These newly formed cells are unadulterated, having not been exposed to years of chronic oxidative stress and other predisposing factors leading to neurodegeneration. Autologous adult neural stem cells represent a new source of cell replacement with identical genetic material to the patient, and mitigate the risks of immune rejections and transmittable diseases generally associated with tissue transplants from a source external to the patient such as HIV, Encephalitis, Hepatitis and Creutzfeld-Jacobs Disease.
CAN STEM CELL THERAPY HELP NEURODEGENERATIVE DISEASES SUCH AS PARKINSON'S DISEASE?
Parkinson's disease is associated with a progressive cell loss of midbrain dopamine-secreting neurons. Dopamine is an essential brain chemical for proper modulation and execution of motor function. Because of the limited spatial involvement and biochemical specificity, this disease may seem relatively easy to repair. Dopamine neurons delivered by fetal transplantation previously were shown to help certain patients with Parkinson's disease, but had significant risk factors, complications, and ethical issues.
The causes of Parkinson's disease remain unknown. Like Alzheimer's disease, there is evidence showing that a combination of environmental factors and genetic predisposition are precursors to the disease. Current animal models, derived from toxic exposure or transgenic manipulation, do no replicate all changes found in the human brain.
In fact, Parkinson's disease is much more complex in human patients because of secondary physiological and chemical changes throughout the rest of the brain, superimposed on long-term medical therapy. Indeed one of the major complications of dopamine drug therapy is the paradoxical creation of dyskinesia, another movement disorder involving uncontrollable thrashing movements.
This complication was also found in some patients receiving fetal transplantation, suggesting that an uncontrolled delivery of excessive dopamine may not be beneficial. Stem cell-derived products have the advantages of being produced under controlled environment and characterized both in their types and function prior to transplantation.
Embryonic stem cells have the potential to generate any type of cells and presumably can be guided in their differentiation to generate an unlimited number of dopamine neurons. One of the problems is to understand the proper steps to guide the gene expression along the formation of neural stem cells and then to achieve proper differentiation.
In addition there remain risks of unstable phenotypic expression, possible transdifferentiation into other types of tissue causing tumors, immune reactions in the host brain and questionable functional benefits. Several additional studies are needed in order to answer these questions and objectively compare these "off the shelf" cell lines to our customized approach using autologous adult neural stem cells.
While the use of somatic nuclear cell transfer (SNCT) technology could decrease risks of immune reactions, this area of research minimizes the importance of "imprinting", or influences of the extra-nuclear material on normal cellular development.
Currently available embryonic cell lines are not appropriate to answer these scientific questions. Embryonic cell therapy has yet to be scientifically proven as safe, if even effective, in human patients.
MATURE NEURONS DERIVED FROM THE PATIENT'S OWN BRAIN CAN BE TRANSPLANTED BACK SAFELY AND IMPROVE SYMPTOMS
We recently presented the clinical outcome of our autologous method at the International Congress of Parkinson's disease and Movement Disorders in Rome. In accordance with our institutional review board, we transplanted a patient with advanced Parkinson's disease with differentiated neurons derived from an initial needle biopsy. At three years post-operatively, the overall Unified Parkinson's Disease Rating Scale (UPDRS) improved by 81% while "on" medication and 83% while "off" medication. We demonstrated here the long-term clinical remission of Parkinson's disease symptoms in a single patient.
Because of their biocompatibility, safety and potential integration into the host striatum, autologous adult neural stem cells and stem cell-derived neurons represent an effective alternative to current cell therapy aimed at the restoration of dopamine neuronal loss in Parkinson's disease. Under the guidance and supervision of the Food and Drug Administration (FDA) office of Cellular, Tissues and Gene Therapies and the Center for Biologics Evaluation and Treatment (CBER) we are about to begin Phase II trials using this promising cell therapy.
Degenerative and traumatic disorders of the brain represent an enormous burden to the patient, their family and health care providers. The current debate between the embryonic stem cell proponents and those who are opposed to their use distracts from other avenues with promising outcome, such as adult stem cell therapy. It also overlooks other important issues of resource allocation between basic and clinical research, health insurance, and patient care.
Scientific knowledge has rapidly progressed in the last five years and stem cell research and therapy remains a very promising field for treatment of neurological disorders. In a recent biotechnology industry meeting, a presentation had the approximate title: "Businesses are from Mars, Academics are from Venus". What was forgotten there is that patients are from planet Earth and this is what should guide our efforts.
Adult human neural stem cells derived from a patient's own tissue can become a source of replacement neurons, useful for grafting in the treatment of neurodegenerative disorders. With time and adequate support this approach has the potential of making neural stem cell therapy acceptable and available to a large number of patients.
Dear members of the committee, I appreciate the opportunity to present our results with the use of human adult neural stem cell-derived neurons and to contribute to an honest and objective debate on these important issues.