Amyotrophic Lateral Sclerosis

ALS stem cell trial


Eva L. Feldman, M.D., Ph.D., is the principal investigator and director of the first-ever FDA-approved human clinical trial in which millions of stem cells are injected directly into the spinal cords of ALS patients. Phase 1 of the trial, designed to study the safety of the procedure, was completed in 2013 with no significant adverse side effects to patients. And follow-up patient evaluations have produced some extraordinary data: Several participants in the trial, who were treated early in their disease, were determined to have had little or no significant progression of ALS for more than 700 days post-surgery.

What began in the lab as the development of neural stem cells and tests on mice has blossomed now into a full-blown human clinical trial. Phase 1 results showed that 18 ALS patients could safely receive the injection of stem cells into their lumbar (lower) and cervical (upper) spinal cords. Now Phase 2, designed to determine whether the stem cells can slow or stop the progression of ALS, has been completed. More than 30 patients have been injected, and the results, while preliminary, are promising.

Intraspinal transplantation of up to 16 million stem cells in patients with amyotrophic lateral sclerosis (ALS) was safe and well-tolerated, and caused no acceleration in disease progression, according to data recently published in the journal Neurology.

Additionally, 70 percent of patients recovered to higher levels than those of the historic control.

Preparations are under way for Phase 2b, which will expand this procedure to 60 new stem-cell recipients.


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University of Michigan ALS Repository

Patients in the ALS Clinic at the University of Michigan are invited to participate in ongoing research projects that will aid in the understanding of disease mechanisms and provide insight into potential therapeutic options.

One study includes the development of the University of Michigan ALS Repository for the Study of Human Disease. Information in this repository includes detailed clinical histories and patient lifestyle profiles, as well as skin and blood samples for use in laboratory research projects. The first aspect of the repository is centered on data collected from a patient occupational and lifestyle survey. We believe that a genetic predisposition combined with specific lifestyle elements (for example, exposure to environmental toxins) contribute to the onset of ALS. Additional details on lifestyle exposures in ALS are detailed below. The second aspect of the repository is patient blood samples. Patient blood samples are collected to investigate the genetics and genetic modifications (epigenetics) which may be involved in ALS. Epigenetics is an important new field of research and we are hopeful that it will aid us in understanding the causes of ALS. More information PNR&Depigenetics projects is detailed below. For the final aspect of the repository, skin samples from ALS patients are being collected to develop induced pluripotent stem cell (iPS) lines. These lines will be used in the laboratory to understand ALS pathogenesis and create models to screen and identify new therapies. Additional information on stem cell research projects, including details on the development and characterization of iPS lines from ALS patients, is detailed below.

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Lifestyle exposures in ALS

We believe that a genetic predisposition combined with specific lifestyle elements (for example, exposure to environmental toxins or diet) contribute to the onset of ALS. Therefore, patients in the ALS Clinic are invited to take an occupational and lifestyle survey so we can gain a comprehensive picture of their various lifestyle elements in order to determine the prevalence of ALS, 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 be a valuable tool when used in conjunction with our laboratory research. This study, if positive, will provide rationale to conduct an epidemiological study on the cause/effect of toxic exposure in ALS in Michigan.

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Epigenetics for ALS

Most cases of ALS cannot be traced to a gene mutation that is passed from generation to generation within a family. Instead, it is believed that most ALS (called sporadic ALS) is the result of long-term influences of environmental factors on the genome. Epigenetics is the field of research that looks at how these environmental modifications on genes change an individual’s biology and contribute to the development of diseases like ALS.

Methylation is a type of reversible epigenetic modification implicated in the regulation of gene function without altering the genetic code (that is, without causing an actual gene mutation that can be passed on to the next generation). Current research in the PNR&D is focused on identifying differentially methylated sites in DNA and RNA extracted from postmortem spinal cord samples from ALS patients to identify modifications altering gene expression. Methylation profiles obtained from this research will be used in the future to detect parallel profiles in blood collected through theUniversity of Michigan ALS Repository to identify epigenetic markers of ALS. This could enable insight into the pathogenetic mechanisms underlying sporadic ALS onset to facilitate the identification of effective therapies, early diagnosis, and potentially early-stage therapeutic interventions to increase survival outcomes in ALS patients.

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Stem cell research projects in ALS

To model ALS, examine disease mechanisms, and screen for novel ALS therapies using stem cell technology, the PNR&D is collaborating with Dr. Ben Reubinoff at the Hadassah University Medical Center in Israel on a project funded by the US-Israel Binational Science Foundation. The project involves generating cellular models of both familial ALS and sporadic ALS using induced pluripotent stem cell (iPS) technology. iPS cell lines are established from ALS patient skin samples, which are collected through the University of Michigan ALS Repository, by introducing transcription factors that revert the cells to a pluripotent, or stem cell-like, state. These pluripotent cells can then be grown in the laboratory and induced to form large numbers of nervous system cells that can be used in numerous types of investigations. While previous cellular and animal models are based on the less common forms of ALS that are associated with a known genetic mutation, these cellular models will provide more broadly applicable insights into the molecular and cellular mechanisms that underlie both familial and sporadic ALS.

At this point, three iPS lines have been developed, and PNR&D investigators are in the process of analyzing and characterizing these lines by inducing them to form spinal motor neurons and astrocytes to model and study how these cells are altered during ALS pathogenesis. This characterization is expected to provide much-needed insight into the mechanisms of ALS onset and progression. This innovative approach allows, for the first time, a cell culture system to examine the mechanisms behind sporadic ALS, which accounts for the majority of ALS cases. The resulting insight into ALS pathogenesis may facilitate the development of new therapeutic approaches for ALS. For example, iPS models of both familial and sporadic ALS may be used for high-throughput screens to identify small molecules that have neuroprotective effects that may then be further developed as novel therapeutic agents for ALS.

PNR&D investigators also are using mouse embryonic stem cells to model ALS. Mouse embryonic stem cells grow quickly, are easy to manipulate, and can be differentiated into motor neurons, the cells that degenerate in ALS. By expressing mutated forms of proteins like SOD1 or TDP43 that are associated with familial ALS cases in these motor neurons, scientists can examine how these mutant proteins affect motor neuron health in order to understand disease mechanisms. One aspect of this work is investigating how posttranslational modifications affect the stability of these proteins and their propensity to form potentially damaging aggregates inside nervous system cells. SOD1 aggregation is found in some familial ALS cases, and TDP43 aggregations are observed in both familial and sporadic ALS cases. Comparing the effects of these different mutations on neuronal health, and understanding what causes aggregations in these cells, will provide important insight into ALS mechanisms.

Finally, the PNR&D is developing stem cell lines that have the potential to deliver therapies to nervous system tissue damaged by ALS. Stem cells not only have the potential to replace damaged neurons and produce supporting factors to improve the spinal cord environment, but they also can be engineered to provide additional supporting factors that could increase the likelihood for nervous system repair. “Enhanced” stem cell lines that produce neurotrophic factors, proteins that can increase the growth and survival of neurons, are being developed and characterized by the PNR&D. Protective roles for the neural stem cell line utilized in the ALS stem cell trial have already been established in multiple preclinical studies in the laboratory, and multiple in-depth analyses from the PNR&D on the efficacy and mechanisms of a neurotrophic factor called insulin-like growth factor-I (IGF-I) have established that IGF-I prevents motor neuron death and improves survival in both cellular and rodent models of ALS. Therefore, given the known benefits of both treatments in preclinical studies, we contend that engineering the neural stem cell line to express increased levels of IGF-I will provide an additional means to augment and protect motor neurons in ALS. Ongoing studies are characterizing the phenotype of these cells and will examine the neuroprotective efficacy in rodent ALS models to generate preclinical support for this novel cellular therapy that has the potential to confer a multifaceted attack on neurodegeneration in ALS.

Overall, the stem cell research program in the PNR&D has the possibility to revolutionize our scientific and clinical approach to ALS by providing new insights into disease pathogenesis and innovative approaches to treat ALS.

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The immune response in ALS

In the PNR&D, we contend that genetic and environmental factors, as well as an altered immune response, contribute to impaired motor neuron survival in ALS. Previous studies hav e demonstrated that the immune system contributes to the ALS pathogenesis; however, most immune studies have utilized mouse models of familial ALS to identify key cellular contributors. Using the University of Michigan ALS Repository, PNR&D are now evaluating the role of innate and adaptive immune cells in human subjects with both familial and sporadic ALS who have provide blood and tissues samples. The goal of this project is to identify biomarkers that will allow us to diagnose ALS, to better assess progression of the disease, and ultimately expand our understanding of ALS pathogenesis.

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MRI imaging techniques for ALS

MRI (magnetic resonance imaging) is a common non-invasive radiology technique that aids in the diagnosis of many neurological diseases and injuries. However, standard MRI techniques typically cannot identify changes in the brains of ALS patients and thus do not help in the diagnosis of ALS. In collaboration with the Department of Radiology, Dr. Feldman is using a new MRI technology available at the University of Michigan ALS Clinic that allows researchers to visualize small molecules in the brain that may be important for ALS onset and progression. This new technique has the potential to provide important insights into brain changes seen in ALS patients that have previously gone undetected or unmeasured. These insights may ultimately reduce the time and difficulty currently needed to make an ALS diagnosis, as well as aid in the design of future therapies.

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Gene therapy for motor neuron diseases

One hurdle to the treatment of motor neuron diseases like ALS is the inability to effectively target therapies to affected cells in the spinal cord. To overcome this hurdle, PNR&D investigators are currently developing and optimizing gene therapy approaches to deliver neuroprotective factors to the nervous system. Gene therapy involves the delivery of genetic material (DNA or RNA) that carries the code for helpful proteins to damaged tissues, where cells can take up the genetic material and begin production of the specific proteins that may support their survival and repair. Using genetically engineered viruses, genes for neural growth factors can be injected into muscles, where they are then taken up by motor neuron axons and transported backwards inside the axons to the cell bodies of the neurons inside the spinal cord. One such growth factor, insulin-like growth factor-I (IGF-I), elicits neuroprotective properties in both cellular and animal models of ALS and can be specifically delivered to motor neurons in the spinal cord using this approach. Similarly, vectors delivering a transcription factor designed to upregulate the neuroprotective growth factor vascular endothelial growth factor (VEGF) in motor neurons have also been successfully developed and are currently being tested in various disease and injury models. Results of ongoing gene therapy techniques in the PNR&D are anticipated to provide a novel, minimally invasive means to administer and target therapies to the spinal cord.

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Studying the head and neck manifestations of ALS

ALS causes not only loss of motor neurons in the spinal cord, but also in a critical area of the brain called the brainstem that control facial and neck muscles. About one quarter of ALS patients develop motor neuron loss in the brainstem first, called bulbar ALS. However, almost all people with ALS will exhibit bulbar symptoms at later disease stages. Loss of bulbar motor neurons results in symptoms that impact the patient’s ability to speak, swallow, and breathe. PNR&D investigators are using an animal model of ALS to study these head and neck manifestations of ALS. The goals of these studies are to determine the causes of these problems and help develop better treatments to improve the quality of life for patients with ALS.