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I. Clinical Trial with Glatiramer Acetate Dr. Przedborski, our Research Director, has promising data that glatiramer acetate (GA, brand name Copaxone) has neuroprotective effects in a mouse ALS model. Dr. Przedborski’s observation was confirmed by Angelov et al ( Proc Natl Acad Sci 2003;100:4790-5), who demonstrated that vaccination with GA prolonged survival significantly in ALS mice. Dr. Przedborski’s research group also found that animal models of Parkinson disease responded favorably to treatment wth GA. Encouraged by these findings, we have initiated a Phase II pilot trial of GA in patients with ALS. This is the first trial of immune modulation in ALS using a vaccination strategy. While ALS is not a primary inflammatory disease like multiple sclerosis, there is growing evidence from Dr. Przedborski and others that there is a significant inflammatory component to motor neuron degeneration. The experimental data indicate that GA suppresses this inflammatory component in neurodegenerative disorders including ALS. We have submitted applications to the appropriate regulatory bodies, including our IRB, the GCRC and the FDA. The study will begin enrolling patients in early Spring, 2004. The inclusion criteria will not be overly stringent so that most ALS patients will qualify. Data from this Phase II pilot study will be used to design and implement a large multicenter efficacy trial. Dr. Paul Gordon, our Associate Medical Director of the Center, is taking the principal role for this project. The major difficulty we are facing using GA is its cost. Despite intense negotiations with Teva Neuroscience, the company has to date refused to provide GA free of charge, because, we are told, Dr. M. Schwartz in Israel, holds a patent for use of GA in ALS. The MDA Wings Over Wall Street Funds are allowing us to circumvent this difficulty, at least for the pilot study. II. Investigation of Upper Motor Neuron Dysfunction The neuroimaging and other ALS biomarker studies are ongoing with the support of the MDA Wings Over Wall Street Research Fund and an NIH grant (Dr. Mitsumoto, our Medical Director, is the Principle Investigator). We have studied a total of 45 patients (31 ALS, 8 PMA, and 6 PLS) to date. Patients with ALS have a repeat study every three months. At the same time, we are acquiring control data from normal volunteers, and we have studied 25 healthy individuals to date. We have generated 5 abstracts (a Work in Progress for the International ALS/MND Symposium, Milan; 2 abstracts submitted to the American Academy of Neurology for presentation in April 2004; and 2 abstracts to the International Society of Magnetic Resonance Medicine). This work is summarized in two of the abstract which are attached to this report. At the same time, we have begun collaborating with Professor Joy Hirsch in a new study of ALS patients using functional MRI. Dr. Hirsch is Director of Columbia’s Functional MRI Laboratory. We are testing the feasibility of imaging simple and complex motor task as a means of identifying and quantifying upper motor neuron dysfunction in patients with ALS compared to normal controls. III. Conference on Clinical Trials in ALS This symposium, held at Tarrytown House and honoring the 100 th anniversary of Lou Gehrig’s birth, was the first of its kind. It proved to be one of the most successful national or international meetings focused on ALS clinical trials. There were 150 participants that included national and international ALS experts, leading biostatisticians, and key representatives from the NINDS/NIH and FDA. The proceedings are being prepared for publication as a supplement to the journal ALS and Other Motor Neuron Disease. About 80% of the manuscripts have been received. The conference was funded in part by the MDA Wings Over Wall Street Research Fund. IV. Genetic and Environmental Epidemiology in ALS We have completed a preliminary study that included developing a standard questionnaire to document family history and environmental exposures. Based on this, MDA has funded a research grant to expand and continue this project. We are planning a consensus conference to help determine the scope of the project and the best protocols to use. This will also give us the opportunity to finalize the questionnaire for environmental exposures and have it accepted for wider use. A tentative agenda for the meeting and a list of proposed investigators and outside consultants are attached. This will be an important step in determining genetic and environmental factors, and their interactions, as the cause of ALS. It is also a necessary step for the large epidemiology study we are planning. “Wings” support has been critical in moving this project forward. V. Other Clinical Research being conducted at the Eleanor and Lou Gehrig MDA/ALS Center Two new projects have been initiated. The first is a validation study of the ALSFRSR scale in 267 patients with ALS seen at our Center. Dr. Petra Kaufmann has assumed primary responsibility for this project. She is working with all investigators at our Center and biostatisticians Dr. Gilberto Levy and Dr. John LP Thompson. The results were presented at the World Federation of Neurology ALS Research Committee and the abstract has also been submitted to the American Academy of Neurology for presentation at the AAN annual meeting in April 2004. This work is particularly important because we are demonstrating that the ALSFRSR score can predict survival in patients with ALS. The other project is a clinical study of primary lateral sclerosis (PLS). This work was initiated by Drs. Paul Gordon, Lewis P. Rowland, and neuromuscular fellow Madelena Pinto. The first step is a critical review of our total experience with PLS. We will then develop diagnostic criteria for PLS. Next, because PLS is so rare, we will establish a multicenter collaboration to accumulate an adequate number of cases. Our ultimate goal is to characterize PLS as completely as possible using clinical, genetic, biological and histological methods. The outcomes will undoubtedly improve our understanding of ALS as well. We are the coordinating center for the NINDS/NIH-funded multicenter minocycline clinical trial, and we are also one of the study centers for the TCH346 clinical trial. We have begun a study using a high-frequency chest wall oscillation device in patients with ALS. Dr. Steven Albert is funded by the NIMH/NIH for a prospective study of psychosocial issues in patients and families living with the terminal stages of ALS. We are also involved with a study of reverse transcriptase in collaboration with Dr. Scott Hammer, and oxidative stress markers in collaboration with Dr. Flint Beal. We have an active ALS brain bank in collaboration with Dr. Arthur Hays. Our own database is the basis of all our clinical studies. We also participate in the national ALS CARE database, and we are among the centers that generate the largest numbers of patients. All of the foregoing research activities have been directly or indirectly supported by the MDA Wings Over Wall Street Research fund. ALS BASIC RESEARCH AT COLUMBIA Dr. Thomas Jessell I. Characterization of Motor Neuron Progenitor Cells The main aim of this project is to define conditions in which motor neuron progenitor cells in mammalian spinal cord can be isolated, grown in vitro, expanded in the presence of mitogenic factors, and then induced to differentiate into motor neurons. II. Directed Differentiation of Embryonic Stem Cells into Motor Neurons In previous studies we have found that it is possible to generate motor neurons from mouse embryonic stem cells, using a simple strategy of exposure of ES cells to retinoic acid and Sonic hedgehog agonists (Wichterle et al. Cell 2002). We are currently extending these observations in the directions. III. Physiology and Function of ES Cell derived Motor neurons in Mammalian Spinal Cord. This project aims to examine the physiological properties of ES cell derived motor neurons after their introduction into neonatal mouse spinal cord, and to examine the capacity of these neurons to innervate target muscle after grafting into peripheral nerve. Dr. Serge Przedborski
The endoplasmic reticulum (ER) signaling pathway, which is activated in reaction to an increased load of unfolded/misfolded proteins, may be instrumental in the demise of motor neuron in ALS. II. Behavior of Motor neurons Derived From Embryonic Stem Cells in Animal Models of ALS Embryonic neural stem cells have emerged as a means to repair the neuromuscular pathway that is degenerated in ALS. This field is still at its very fist phase and many essential questions with respect to the basic biology of neural stem cells remain to be addressed prior to embarking in neural stem cell repair interventions. Dr. William Dauer I. Generating and Characterizing an Inducible Model of ALS We have succeeded in generating all of the necessary constructs for both strategies (“cis” and “trans”) as originally proposed. These constructs were injected (some multiple times) by the Columbia University Transgenic Core Facility. Founders were obtained for all lines, and the mice were characterized as detailed below. |
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