Current Research: ALS
- The First Stem Cell Trial for ALS Treatment Wins FDA Approval
- Zebrafish as a Model Organism for ALS
- Computational Analysis of SOD1
- Innovative Treatment for ALS Using VEGF
- The Role of Environmental Toxins in ALS
The first stem cell trial for ALS treatment wins FDA approval
New therapy that U-M neurologist helped develop will undergo Phase I trial at Emory University
U.S. Food and Drug Administration gave the green light Friday for a clinical trial of a new stem cell treatment for amyotrophic lateral sclerosis (ALS). University Michigan neurologist, Eva Feldman, M.D., Ph.D., will be the overall principal investigator for the first human clinical trial of a stem cell treatment for ALS, a fatal neurodegenerative disease.
The FDA approved an Investigational New Drug application from Neuralstem, Inc., a Rockville, Md.-based biotech company, to test the safety of a treatment in which patients will receive injections of the company’s patented neural stem cells at multiple sites along the spinal cord.
Director of the U-M ALS Clinic and the Director of the Program for Neurology Research & Discovery, Feldman worked with a team of neurologists and with Neuralstem Inc. to develop the protocol for delivering the stem cells into the spinal cord of patients.
The Phase 1 trial to determine the safety of the treatment is expected to take place exclusively at Emory University in Atlanta, Ga., subject to approval by its Internal Review Board.
“We are very excited about this clinical trial,” said Feldman, the DeJong Professor of Neurology at the U-M Medical School. “This is a major stride forward in what still could be a long road to a new and improved treatment for ALS.
“ALS is a terrible disease that ultimately kills by paralysis. In work with animals, these spinal cord stem cells both protected at-risk motor neurons and made connections to the neurons controlling muscles. We don’t want to raise expectations unduly, but we believe these stem cells could produce similar results in patients with ALS,” Feldman said.
ALS, also known as Lou Gehrig’s disease, affects about 30,000 Americans. It progressively destroys the neurons that control voluntary muscles, leaving affected people unable to move or speak. There are no known treatments for the disease that slow its progression.
The trial will ultimately consist of 18 ALS patients with varying degrees of the disease. The FDA has approved the first stage of the trial, which consists of 12 patients who will receive five-to-ten stem cell injections in the lumbar area of the spinal cord. The patients will be examined at regular intervals post-surgery, with final review of the data to come about 24 months later.
Jonathan Glass, M.D., director of the Emory Neuromuscular Laboratory, is expected to be the site principal investigator for the trial.
Individuals interested in further information on the trial should contact Emory Health Connection, 404-778-7777, or 1-800 75EMORY, or go to www.neurology.emory.edu/als
Institutional review boards at U-M and Emory University must first approve the protocol.
If Phase I results are favorable, the treatment will need to prove effective in Phase II and III trials and win final FDA approval before it can be available for public use.
Funding: Neuralstem, Inc. plans to conduct and fund the Phase I trial of its patented technology. Patents/conflict disclosures: Dr. Feldman has no financial interest in or financial arrangement with Neuralstem.
Zebrafish as a Model Organism for ALS
Zebrafish as a model organism provide many advantages over mouse and rat models for studying disease causes and for discovering new therapies. Zebrafish are vertebrate organisms that are very similar to mammals in their development and physiology, but they develop very quickly. Large numbers of embryos are obtained on a weekly basis and they are fertilized externally. Zebrafish are easy to observe early in development because they are transparent, and potential therapies can be tested on zebrafish by simply adding the compounds to the water. Lastly, zebrafish genes can be easily manipulated to create disease models.
The ALS zebrafish model is generated by expressing mutant SOD1 in the embryos, a mutation associated with familial ALS. These mutant SOD1 zebrafish have motor neurons with observable defects. Using zebrafish as a model organism for ALS will allow us to understand the effects of mutant SOD1 on motor neurons and identify changes in the motor neurons that could be used to diagnose the disease earlier. Zebrafish will also enable us to screen large numbers of potential therapeutic factors, and combinations of these potential therapeutic factors, to identify new beneficial treatments for ALS.
Computational Analysis of SOD1
Familial amyotrophic lateral sclerosis (fALS) is caused by mutations of the Cu-Zn superoxide dismutase 1 (SOD1) protein. SOD1 maintains its antioxidant activity under these fALS causing mutations, thus suggesting that the mutations introduce a new, toxic, function. We developed a pair of complementary computational methods for elucidating a component of the toxic mechanism.
The first method is based on the static conformation of the healthy, wild type (WT) form and indicates an inherent network of connectivity within the structure. This network is a foundation which allows for internal structure communication. The second method identifies the accessible motions of the WT and mutant structures. A comparative analysis of these motions reveals motions that are preferred by the mutant structures compared to the WT.
Our hypothesis is that the preferred motions induced by the disease causing mutations are able to communicate across the structure and introduce a toxic function.
Innovative Treatment for ALS using VEGF
This study, if positive, will provide the fundamental basis for the use of stem cells in the treatment of neurological disorders such as ALS.
Dr. Andrea Vincent & Dr. Bhumsoo Kim
Vascular endothelial growth factor (VEGF) controls new blood vessel growth. In the nervous system, however, it also supports the growth and survival of neurons. Mice lacking the ability to increase their VEGF levels experience a condition which appears almost identical to amyotrophic lateral sclerosis (ALS) in humans. In addition, studies of VEGF in 600 individuals with ALS and 1,000 case-controls have shown that decrease in VEGF levels can increase the risk of developing ALS by nearly double. These findings suggest that VEGF may eventually be used as a therapy for ALS. One practical problem with using VEGF as a therapy in patients is that cells produce multiple types of VEGF, and a combination of these types is required for VEGF to produce effects. To get around this problem we are working with Sangamo Biosciences, Richmond, CA to develop a new way to increase VEGF activity in the nervous system using gene therapy.
This project has three primary goals:
- Examine the effects of VEGF on motor neurons in culture.
- Test the effect of our gene therapy approach on production and bioactivity of VEGF.
This study, if positive, will provide rationale to define the theraputic potential of VEGF as a treatment for ALS. A grant has been submitted to the National Institutes of Health, R01 NS 051705 entitled "VEGF as a treatment for ALS."
The Role of Environmental Toxins in ALS
ALS (amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease) is a disease characterized by the deterioration of motor neurons in the brain and spinal cord. Approximately 10% of ALS cases are due to genes inherited within families. The cause of the remaining 90% of ALS cases is still unknown. No treatment is currently available to significantly slow or halt the progress of this disease. We believe that a genetic predisposition combined with specific lifestyle elements (e.g., exposure to environmental toxins, athletic/physical exertion, or diet) contribute to the onset of ALS. We are currently addressing this question in a combination of ways:
CELLULAR STUDIES
First, through cellular studies, we are attempting to identify classes of toxins in the environment that affect the nervous system (neurotoxins), and mediate motor neuron injury. Neurotoxins produce cellular damage in a variety of ways, all of which are dangerous to cells. By screening FDA approved drugs in our primary motor neuron models, we test the hypothesis that specific classes of neurotoxins create motor neuron injury.
ANIMAL STUDIES
Second, by studying a mouse model of clinical ALS, we investigate numerous aspects of the disease. We are examining the effects of exercise stress and distinct classes of neurotoxins on motor neurons. In addition, we hope to identify the genes that account for the variations between genetically similar mice that inhabit the same environment. Understanding which genes cause the differences would provide tremendous insight into the injury of motor neurons, as well as provide potential targets for therapy. These goals are all designed to determine whether neurotoxins or exercise stress worsen motor neuron injury.
POPULATION STUDIES
Finally, we must conduct a comprehensive study of ALS in the population. Although it would seem an obvious initial step, too little has been done to compile information about ALS cases in the state of Michigan and elsewhere. The aim of such a study is to determine the prevalence of ALS, examine its causes, identify possible common factors, and study a potential correlation between ALS and toxic exposure in Michigan. This project is the first attempt to systematically examine ALS cases and determine whether any clusters of the disease exist that would indicate specific environmental causes. The information gathered from this project will prove to be a valuable tool when used in conjunction with our laboratory research. A study of this type will also assist in the improvement of the public health response to ALS.
This study, if positive, will provide rationale to conduct an epidemiological study on the cause/effect of toxic exposure in ALS in MI. A grant has been submitted to the National Institutes of Health, NIH RO1 entitled "The role of environmental contaminants in ALS."
