ALS Association Announces New Research Grants for 2010

The ALS Association has announced newly-funded research grants for the August 2010 cycle.  Our TREAT ALS Portfolio (Translational Research Advancing Therapies for ALS) is a research endeavor enabling important research to progress from the laboratory to the bedside. The focus of the program is to support novel ideas, build tools, partner with industry to identify new potential therapies and support the infrastructure for clinical trials, with the goal to find meaningful treatments for ALS and a cure.

In addition, through the Milton Safenowitz Post-doctoral Fellowship program, young scientists are encouraged to focus their interest in ALS research.  New research studies funded this year will focus on areas of stem cell research, genetics, therapy development, biomarkers and neuroinflammation. Three new Milton Safenowitz Postdoctoral fellows will focus on the genes recently identified for familial ALS, TDP43 and FUS; new techniques to identify genes for familial ALS; and a novel triple transgenic mouse to identify the role of inflammation in ALS.

Novel Surgical Approaches to Stem Cell Transplantation for ALS

Clive Svendsen, Ph.D. Cedar-Sinai, Los Angeles, CA

Presently there is one clinical trial at Emory University injecting stem cells produced by the company Neuralstem into the spinal cord of patients with ALS. This project uses a very invasive but accurate injection method where a frame is placed on the patient under deep anesthesia and a large portion of the spine is exposed in order to target the appropriate region for transplantation.

This study, however, uses a much simpler and non invasive approach for stem cell delivery based on a modified lumbar puncture technique. An outer guide needle is positioned in close proximity to the spinal cord, and an inner needle containing the cells is pushed under imaging guidance into the target area and cells are then injected. The investigators have developed a clinical grade neural stem cell line that secretes a powerful growth factor, GDNF. They plan to inject these cells using this procedure in a number of pigs under conditions where the data can be used for presentation to the FDA and then progression to a clinical trial.

Bone marrow-derived cells as gene delivery vehicles in ALS

Charles Krieger, Simon Fraser University, British Columbia, Canada

Fabio M.V. Rossi, Biomedical Research Center, University of British Columbia, Canada

The use of bone marrow-derived cells as a novel therapeutic delivery system has considerable promise in the treatment of ALS. Bone marrow-derived cells can be injected into the circulation, and there is evidence from pre-clinical studies that these cells are capable of entering the brain and spinal cord under some conditions. The investigators’ previous work has shown that bone marrow cells enter the brain and spinal cord in an animal model of ALS.

In this work they will engineer the population of bone marrow cells that enter the central nervous system to produce growth factors such as vascular-endothelial growth factor (VEGF) within the nervous system to permit delivery of growth factors directly to brain and spinal cord. They anticipate that these growth factors will aid in the survival of diseased neurons. They will identify which bone marrow-derived cell types enter the nervous system so that we can restrict the production of growth factors only to the specific bone marrow population that enters the nervous system. Knowing the relevant cell populations will allow them to restrict production of the secreted growth substances which will minimize the adverse effects of using the engineered cells.

Genetics of amyotrophic lateral sclerosis in different ethnic groups of sporadic patients of Jewish origins and in groups of patients with specific clinical characteristics.

Vivian E Drory, M.D. Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel

Amyotrophic lateral sclerosis (ALS) is a disease caused by many different factors, among them genetic and environmental factors. Genes can not only directly cause disease, as in familial ALS, but can also be disease modifiers in the more frequent sporadic (non-familial) form. One of the latest developments in genetic research is the whole genome analysis technology, which allows screening of most parts of the human DNA for comparison between patients and healthy individuals.

It is well recognized that isolated populations are advantageous in genetic studies in order to detect increased risk of disease. The Jewish population has maintained relatively closed communities for many hundreds of years, therefore preserving its unique genetic characteristics. Due to changing life styles, today's generation of patients is probably the last one maintaining a relatively homogenous ethnic origin and represents a unique opportunity to study genetic influences in this ethnic group.

The investigators intend to perform a whole genome analysis in a clinically well characterized group of Ashkenazi Jewish patients with ALS and controls and replicate findings of novel genes associated with ALS risk or protection in a larger pool of Jewish patients of different ethnic backgrounds.

Butyrate-based Neuroprotectants as Therapeutics for Amyotrophic Lateral Sclerosis

Matthew E. R. Butchbach, Ph.D., Ohio State University, Columbus, OH

ALS is a devastating motor neuron disease characterized by progressive motor dysfunction and degeneration of corticospinal motor neurons. Transgenic rodent models for a subset of familial ALS case involving mutation in SOD1 have been generated. Work from others has shown that administration of 4-phenylbutyrate to SOD1 (93A) transgenic mice improves their survival by ~21%.

The investigators have tested a series of butyrate-based compounds that result in a marked improvement in survival and motor phenotype of severe spinal muscular atrophy mice. These phenyl/butyrate prodrugs are more potent, have more favorable pharmacokinetic properties, and can easily penetrate the blood-brain barrier. In this project, investigators propose to test these compounds in transgenic mouse models for ALS. These compounds, therefore, will be more potent therapeutics for ALS, which can be moved forward into clinical trials.

Nmnat-mediated axonal protection in ALS

Jeffrey Milbrandt, Washington University School of Medicine, St. Louis, MO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive paralysis caused by the loss of upper and lower motor neurons in the brain and spinal cord. Like other neurodegenerative diseases, it appears that axonal degeneration is an early event in ALS that occurs prior, and directly contributes to the motor neuron cell death observed as the disease progresses. As such, axonal degeneration appears to be an important contributor to the morbidity associated with ALS.

From studies of wlds mutant mice, which manifest delayed axonal degeneration after nerve injury, the investigators recently demonstrated that axonal degeneration can be suppressed by increased expression of Nmnat1, an enzyme that synthesizes NAD, a central regulator of cellular metabolism. In this proposal, they will test whether activation of the Nmnat enzyme will prevent motor neuron degeneration and disease progression in a mouse model of ALS, and whether it can prevent axon degeneration caused by human mutations associated with ALS. If successful, this will highlight axonal degeneration as a therapeutic target in ALS, and stimulate the development of new treatments for ALS-based on manipulation of Nmnat activity.

Molecular genetic analyses of novel and known genes implicated in ALS and ALS-FTD

Dr. Rosa Rademakers Mayo Clinic, Department of Neuroscience, Jacksonville, FL

In the past few years, it has become increasingly recognized that amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are diseases with overlapping clinical and pathological features. ALS and FTD often present in the same families, and it has been estimated that the prevalence of dementia in ALS populations may approach 40%. Interestingly, the TAR DNA-binding protein (TDP-43), a novel nuclear DNA and RNA binding protein, was recently identified as the disease accumulating protein in both FTD and ALS patients, further supporting the pathological overlap between these disorders.

The research proposed in this grant is based on the hypothesis that ALS and FTD are part of a spectrum of diseases with common genetic factors contributing to their development. Significant advances have been recently made towards the identification of genes for FTD, and the investigators propose to study the genetic contribution of these genes in ALS. In addition, they aim to identify a novel gene for a combined phenotype of ALS and FTD, which is known to be located on chromosome 9p. A better knowledge of the genetic causes of ALS will lead to improved diagnosis, more effective genetic counseling and will facilitate the development of therapeutic strategies.

Activated protein kinase C in ALS SOD1-mutants

Berislav Slokovic, University of Rochester, Center for Neurodegenerative and Brain Disorders, Rochester, NY

Amyotrophic lateral sclerosis (ALS) is a chronic progressive degenerative disorder of the nervous system resulting in a progressive muscular weakness and paralysis that kills individuals within 3-5 years of onset. Most cases of ALS are sporadic, but about 10% of patients have a familial history. Genetic changes (mutations) in an enzyme superoxide dismutase-1 (SOD1) are the most common form of inherited ALS. Recent work suggests that abnormal SOD1 species are linked to most cases of sporadic ALS.

A convergence of evidence has lead to a consensus that changes in SOD1 cause disease from acquisition of one or more toxic properties. Here, investigators propose a novel approach to suppress and eliminate aberrant SOD1 species in the spinal cord by using another enzyme known as activated protein C (APC). The investigators’ pilot data show that APC blocks the appearance of abnormal SOD1 in a mouse model of ALS and in cells expressing different abnormal forms of SOD1. The investigators hope that if their pre-clinical studies are successful that APC-based therapy can be extended to patients with ALS. APC has been approved by FDA for treatment of patients with severe sepsis and is currently being studied in patients with stroke as a brain protecting agent.

Mass Spectrometry Imaging of Motor Neurons and Their Environment

Jeffrey Agar, Brandeis University Rosenstiel Center, Waltham, MA

The investigator’s goal is to better understand the motor neuron, the molecules and cells that surround it, and how these relate to Amyotrophic Lateral Sclerosis (ALS) etiology. ALS results from the death of spinal cord motor neurons, but the cells surrounding motor neurons do not die. Moreover, these surrounding cells are not innocent bystanders, but in fact contribute to the death of motor neurons. Understanding ALS therefore requires characterizing the “neighborhood” of motor neurons.

The investigators use a mass spectrometer equipped with a focused laser to selectively analyze and compare hundreds of proteins and lipids from motor neurons or the cells that surround them. Elucidating ALS-related changes in the protein and lipid composition of motor neurons and neighboring cells enables us to understand their relationship in molecular terms. This relationship can be studied by comparing “normal” and ALS model mice, or by studying a given tissue region as function of disease progression. Proteins or lipids that are discovered to change as a result of ALS are referred to as biomarkers and are potentially targets for therapeutic intervention as well as markers that can measure drug efficacy.

The Milton Safenowitz Post-Doctoral Fellowship for ALS Research

Three young investigators funded by The Milton Safenowitz Post-Doctoral Fellowship for ALS Research are engaged in innovative projects to accelerate progress in the field. The ALS Association is especially committed to bringing new concepts and methods into ALS research, and young scientists play an important role in this process. Funding is by the generosity of the Safenowitz family through the Greater New York Chapter of The ALS Association, in memory of Milton, who died in 1998 of the disease.

Whole exome capture and parallel DNA resequencing of Familial ALS cases

Hussein Daoud, Ph.D. Center of Excellence in Neuromics, Montreal, Canada

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that leads to a progressive paralysis due to the death of large motor neurons in the brain and spinal cord. While the discovery of several genes, notably SOD1, TARDBP and FUS has led to significant new insights into the causes of ALS, the basic pathogenic mechanism and the genetic etiology of most ALS cases remain unknown. Most importantly, the genetic cause of more than 50% of familial ALS cases (FALS) remains to be identified. Therefore, it remains important to identify additional ALS-causing genes and converging evidence suggests that a large number of rare, highly pathogenic, mutations underlie a substantial fraction of the familial form of the disease.

Such rare mutations cannot be identified using whole genome association methods as their identification rather requires a direct resequencing of patient DNA. The investigators propose to use modern and powerful DNA sequencing methods available to their group and expand the genetic screen analysis to the entire coding genome by resequencing all the coding exons, or “exome”, in a cohort of 60 unrelated SOD1, TARDBP and FUS negative FALS patients (and unaffected relatives), which will be selected from their largest and clinically well defined affected families.

Understanding the landscape of neuroinflammation and identification of key players using MCP1- CCR2-SOD1G93A triple transgenic mice in vivo

Javier Jara, Ph.D., Northwestern University, Chicago, IL

In ALS motor neurons in the cortex, brainstem and spinal cord show vulnerability, and progressively degenerate. Cells that initiate an immune response both locally and broadly in the system are suggested to play a role in ALS disease. These cells secrete molecules called cytokines, which have a wide variety of functions from immune response to neuronal protection. We still do not know what exact role these cells have on disease initiation and progression and how cytokines are involved in the process. If we have a clear understanding of the system and the role of each player, we can then build effective treatment approaches in ALS.

The investigators have generated a triple transgenic ALS mouse model, in which the cytokine (MCP-1) and its receptor (CCR2) are genetically labeled with red and green fluorescence, respectively. Using this mouse model they will overcome two major limitations in the field: 1) They will visualize their cellular interactions with the vulnerable motor neurons both in the cortex and spinal cord over time, and 2) they will isolate and purify them to further investigate and identify the subset of molecules that are involved in local and broad immune reaction in ALS. This is novel and very important for the future development of treatments.

Determining non-cell autonomous contributions of TDP-43 and FUS mutations in ALS using embryonic stem cells

Dara Ditsworth, Ph.D. Ludwig Institute for Cancer Research, UCSD, San Diego, CA

The recent identification of mutations in TDP-43 and FUS in both sporadic and familial cases of ALS suggests that alterations in RNA processing may play a pivotal role in ALS pathogenesis. In addition to these mutations, TDP-43 and FUS have been identified as components in the pathology of several neurodegenerative diseases. Whether disease-associated mutations lead to the loss of an essential normal function or the gain of a toxic new function remains unclear. Furthermore, whether mutations in TDP-43 or FUS affect other cell types that contribute to motor neuron disease progression is unknown.

The investigators aim to explore consequences of the loss or gain of function mutations in TDP-43 and FUS by using embryonic stem cells from existing transgenic mice and inducing differentiation into motor neurons or glia. Combined with cutting edge technology to analyze global alterations in gene expression, these aims will address basic questions in isolated cell populations or in mixed cultures of motor neurons or glia. It is their hope that this work will lead to greater understanding of disease mechanism, and may provide rationale for future studies of whether manipulation of supporting glial cells would provide therapeutic benefit in patients with mutations in TDP-43 or FUS.