ALS Research Projects: Grants on the Rise

To date, the Robert Packard Center for ALS Research at Johns Hopkins has awarded 106 research grants and has several new grants pending, at a total cost of close to $21.2 million. The Center awards ALS research grants throughout the year on a flexible time frame, with the idea that rapid funding fosters innovative ideas. 

Acevedo-Arozena | Becker | Bedlack | Brown | Burden | Farah | Gitler | Glass | Goldberg | Julien | Lechtzin & Yuhas | Manfredi | Maragakis | Miller | Morimoto | P²ALS | Pandey | Robberecht | Traynor | Wang | Wong | Wong | Zou

Abraham Acevedo-Arozena, PhD 

Medical Research Council, Oxford UK
Characterization of a unique mouse model of ALS

We are characterizing a new, unique mouse model of amyotrophic lateral sclerosis (ALS). This new model carries a point mutation in the mouse SOD1 gene that is identical to human cases of familial ALS. This is the first mouse model carrying this specific mutation in SOD1 that develops motor neuron degeneration and we will be undertaking in depth phenotypic characterization of these new mice to understand the human condition. The mice are a new and important model because they are likely to mimic the biochemistry of the human condition better than existing transgenic mice.

Catherina Becker, PhD

University of Edinburgh
Generation and Integration of New Motor Neurons in the Adult Spinal Cord of Zebrafish  

Co-funded with University of Edinburgh

Humans cannot replace motor neurons that are lost in ALS. However, we have found that zebrafish, an important animal model, readily replace motor neurons from adult stem cells that are already resident in the damaged spinal cord. By identifying the molecules involved and showing how the mechanism of motor neuron regeneration in zebrafish can be controlled, our studies will inform future therapies aimed at rescuing or replacing diseased motor neurons in ALS.

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Richard Bedlack, MD, PhD

Duke University
ALSUntangled

Patients with ALS sometimes consider alternative or off-label treatments for their disease. It is difficult, however, to get accurate information on their costs, side effects and potential benefits. We will use email, Twitter and other social media to bring patients, clinicians and scientists together to document the facts about various alternative and off-label therapies being offered for ALS.

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Solange Brown, MD, PhD

Johns Hopkins University
Inhibitory Cortical Circuits in Presymptomatic ALS

One of the hallmarks of ALS is the death of upper motor neurons in the cerebral cortex. However, it is not known whether more subtle changes in cortical circuits precede upper motor neuron degeneration. We propose to study the excitatory and inhibitory neurons of the motor cortex, and their patterns of connectivity, to determine whether functional changes in these circuits represent early events in the development of the disease. The goal of this work is to identify primary events in the disease process that can suggest new preventative strategies and therapeutic targets in ALS. Furthermore, combining this work with the studies of lower motor neurons will give a fuller picture of why motor neurons are particularly vulnerable in ALS.

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Steven J. Burden, PhD

New York University
Prolonging longevity and maintaining neuromuscular synapses in SOD1 G93A mice by increasing MuSK expression/activity

Our prior experiments demonstrate that a modest increase in MuSK expression is sufficient to maintain compromised neuromuscular synapses and raise the possibility that increasing MuSK expression/activity in other circumstances, including ALS, may prevent or delay motor axon withdrawal and extend longevity. We propose to determine whether increasing MuSK expression is sufficient to prolong longevity and delay motor axon withdrawal in SOD1 G93A transgenic mice.

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Mohamed H. Farah, PhD

Johns Hopkins University
New tools for the assessment of pathology and therapeutic responses in models of motor neuron diseases

This renewal project will continue the work of Packard scientist Dr. John W. (Jack) Griffin, who passed away untimely earlier this year. Dr. Griffin identified the lateral thoracic nerve/cutaneus maximus muscle (LTN/CMM; Griffin et al., 2010) as a system that has unique advantages for visualization and electrophysiological analyses of motor nerve and neuromuscular junction degeneration. We propose to carry out detailed morphological studies and electrophysiological analysis of the LTN/CMM system in a G93A SOD1 mouse at early stages of axon terminal degeneration. The goal is to thoroughly characterize the CMM/LTN system in SOD1 mouse model and identify the earliest degenerative events in order for the method to be widely adopted in future studies to aid in much higher throughput of pathogenetic analysis and therapy development in the field.

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Aaron Gitler, PhD

University of Pennsylvania
Novel Yeast and Zebrafish Models to Explore the Role of FUS/TLS in ALS

In motor neurons of both humans and many animal models of ALS, it's not uncommon to find abnormal clumps, or aggregations, of several proteins. Gitler and Granato propose to study the biology of one of them, a protein that's generated by the FUS/TLS gene. Using yeast cells as easy-to-study model systems, they hope to learn how and why the FUS/TLS protein forms clump within cells and how that's related to motor neuron death. Other work involves studying FUS/TLS in zebrafish, which are both fast-dividing and transparent, enabling easy study.

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Jonathan Glass, MD

Emory University
Novel Therapeutic Interventions in the fALS Mouse

Our earlier Packard work showed that the degeneration of a motor neuron's leading end, the most distant part of the extending axon, is one of the earliest changes in the SOD1 mouse that models ALS. This is likely the same in human disease.

The work has prompted studies by other Packard investigators, and those outside of Packard, to focus on this area as a possible seedbed of ALS . We, ourselves, have advanced this field by studying how the mutant SOD1 gene – a source of human familial ALS – carries out this distal motor neuron damage. We've examined the phenomenon of having an excess of free radicals – oxidative stress – in motor axon degeneration, and have been studying the importance of normal SOD1 within the mitochondria, the cell's powerhouses, in keeping distal motor axons healthy.

While we are continuing our study of axonal oxidative stress, this latest grant work aims to clarify why motor neurons, specifically, are so vulnerable in this mouse model of human familial ALS.

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Alfred Goldberg, PhD

Harvard University
Mechanisms for stimulating autophagy and proteasomal degradation to clear misfolded proteins

ALS, like several other major neurodegenerative diseases, results from a buildup in the affected neurons of misfolded proteins, whose accumulation is toxic. Our studies build upon recent insights about the mechanisms cells naturally use selectively to destroy such misfolded proteins. We aim to investigate molecular pathways we could manipulate to enhance the neuron’s ability to degrade such dangerous molecules and, thus, to prevent disease progression.

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Jean-Pierre Julien, PhD

Laval University, Quebec
Intrabody-based therapy for blocking TDP-43 interaction with NF-?B p65

We recently discovered that an upregulation of TDP-43 in ALS acts as co-activator of nuclear factor-?B (NF-?B), which can induce hyperactivity of NF-?B resulting in exaggerated innate immune responses and increased neuronal vulnerability to toxic environment. Here we propose to develop a therapeutic approach that uses intracellular antibodies (intrabodies) that work in the nucleus to block the specific interaction between TDP-43 and a small piece of NF-?B known as p65. First, we will use a hybrid of two different cell culture lines to generate monoclonal antibodies against the N-terminal domain and RRM1 domains of TDP-43. Then, from the appropriate hybrid cell lines we will derive small pieces of DNA to generate intrabodies using an adeno-associated virus to block TDP-43 and p65 interaction in the nucleus, thereby alleviating ALS.

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Noah Lechtzin, MD & Ben P. Yuhas, PhD

Johns Hopkins School of Medicine / Yuhas Consulting Group, LLC
Identifying Interactions Between Prescribed Drugs and Survival Rates of ALS Patients Using Medicare Data

Our objective is to demonstrate the usefulness of studying Medicare claims data to provide insight in making prognoses for ALS patients. We’ve proposed a pilot study to look at the relationship between prescribed drugs and survival rates in ALS and to determine if that warrants a more comprehensive investigation.

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Giovanni Manfredi, MD, PhD

Weill Medical College, Cornell University
Mitochondrial involvement in TDP-43 mutant mice

Mitochondria provide neurons with the energy necessary for their function and survival. In ALS, mitochondria degenerate, and fail to provide adequate energy supplies to cells, thereby participating to their death. Our current knowledge on mitochondrial dysfunction in ALS is mostly limited to familial forms of the disease with SOD1 mutations, but new evidence links mitochondrial abnormalities with another form of familial ALS associated with TDP-43 mutations. In this application, we propose to apply our expertise on mitochondrial biology to understanding how mitochondrial dysfunction is involved in the disease, in a TDP-43 transgenic mouse model. We will characterize the bioenergetics and dynamics of neuronal mitochondria and their ability to control the levels of calcium, a fundamental ion that regulates vital cellular functions.

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Nicholas Maragakis, MD

Johns Hopkins School of Medicine
A non-neuronal, human cell-based transplantation paradigm targeting respiratory dysfunction in ALS

Funding for this project was made possible by the Muscular Dystrophy Association

Most ALS patients die from respiratory failure as the muscles that control breathing become weak. While many cell transplantation strategies have focused on replacing the motor neurons that service those muscles, our work focuses on use of human glial stem cells to protect the motor neurons in the first place. We're exploring this first by transplanting glial stem cells into a rat model of ALS. The cells are targeted to the neck region of the spinal cord - the area containing motor nerves that innervate breathing muscles. Measurement of various signs will show if disease course has slowed. Our hope is that that targeting these specific regions will ultimately lead to human glial stem cell trials aimed at significantly prolonging patients' lives.

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Timothy Miller, MD, PhD

Washington University in St. Louis
Determining and blocking miRNA changes in activated microglia in vitro and in ALS mice

Cells in the spinal cord known as microglia can become activated during amyotrophic lateral sclerosis. These cells are also involved in inflammation and appear to accelerate disease progression. We have determined part of the genetic program underlying the activation of inflammatory pathways in microglia. We will attempt to block this genetic program as a way to slow down progression of disease in an animal model of ALS, and then translate this type of therapy to treatment of human ALS.

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Richard Morimoto, PhD

Northwestern University
The Proteostasis of ALS

The focus of my current project is to understand how organisms sense and respond to physiologic and environmental stress through the activation of genetic pathways that integrate stress responses with a variety of molecular and cellular responses. We believe that the expression of ALS-associated proteins (SOD1, TDP-43 and FUS) interferes with protein homeostasis (proteostasis) leading to the failure of dynamic cellular processes. To address this, we propose to establish new genetic models for expression of these proteins for direct comparison of the biochemical, biophysical, cellular, and physiological properties during C. elegans development and aging. These experiments will establish whether aggregates of ALS-associated mutant proteins shut down essential cellular functions.

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Udai Pandey, PhD

Louisiana State University
A Drosophila Model to Investigate the Role of FUS in ALS

ALS is marked by abnormal accumulations of a protein named FUS/TLS. In creating fruit flies (Drosophila melanogaster) that carry the human FUS/TLS gene, we've found an economical, easily-studied model of ALS. Our goal with this Packard grant is to understand how the FUS/TLS gene promotes the disease in Drosophila. What we discover, we assume, will shed clearer light on both familial and sporadic ALS in patients.

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Wim Robberecht, MD, PhD

University of Leuven, Belgium
Validation of the use of a zebrafish model as a screening tool to identify modifying genes in Amyotrophic Lateral Sclerosis

Using a zebrafish model to study the mechanism of ALS, we have identified a gene called ephA4 which rescues the motor abnormalities induced by mutant SOD1. We now intend to investigate the role of this gene in ALS and want to study whether genetic alterations in this gene are associated with ALS in humans. Furthermore, we want to explore the therapeutic potential of interfering with this receptor.

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Bryan Traynor, MD

National Institute on Aging, NIH
ALS gene discovery using exome sequencing
   

This Packard grant was awarded to employ a new technique, exome sequencing, to find the single, mutant genes that underlie familial ALS. These familial genes will also be be screened in the commoner sporadic form of disease. The overall result, then, will be identification of genes underlying ALS.

The technique centers on ultra-new technology that can rapidly sequence DNA, and directing it to single out those areas of the human genome that code for proteins. (This key part is called the exome and makes up about 1 percent of the human genome.) Within three months of obtaining funding, we should be able to fully sequence 21 exomes. The sequence data we derive from this project will be made available on a public website, offering a much-awaited resource for ALS researchers worldwide.

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Jiou Wang, MD, PhD

Johns Hopkins University
Using C. elegans to Investigate Molecular Mechanisms of ALS

Funding for this project was made possible by the Muscular Dystrophy Association

Our laboratory seeks to use the small, soil-living, transparent roundworm – Caenorhabditis elegans – as a model organism to clarify how disease genes cause ALS in humans. Like the fruitfly, C. elegans is used by researchers to investigate how both healthy and mutated genes affect function. With its fast growth rate and the amount of knowledge we already hold about its genome, the tiny animal – it's about the width of a pencil lead – provides a unique system to study aging related diseases.

Recently, we genetically engineered C. elegans to model one specific form of inherited ALS (that with mutant SOD1 genes). Using the C. elegans model, we were able to conduct unbiased, large-scale screens to search for uncommon genes that might slightly raise the risk of having the disease. Now we aim to establish new C. elegans models of ALS linked to those mutations in patients. We hope that our studies will reveal important disease pathways in humans, and thus provide potential drug targets.

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Philip C. Wong, PhD

Johns Hopkins School of Medicine
Generation and Characterization of Wildtype and ALS-linked FUS/TLS mice

Funding for this project was made possible by the Muscular Dystrophy Association

The discovery of mutations in a gene encoding an RNA binding protein (FUS/TLS) linked to both sporadic and familial ALS provides the opportunity to further our understanding of the underlying cause of this illness. In this proposal, we plan to study the effects of an ALS-associated mutant FUS/TLS protein in transgenic mice and identify any resulting motor neuron disease. If disease results, this mouse model will help clarify the behavioral and pathological signs associated with ALS onset and disease progression. These transgenic mice will also help with the design of therapeutic strategies to attenuate this devastating disease.

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 Philip C. Wong, PhD

Johns Hopkins School of Medicine
Physiological Role of TDP-43: development of conditional TARDBP knockout mice

How ALS arises in sporadic ALS patients remains elusive. We believe the recent discovery of mutations in the TDP-43 gene  – one linked both to sporadic and familial ALS – will help lead us to understand the cause.

To do that, it’s first necessary to determine what part the gene’s product, a protein also called TDP-43, plays in motor neurons. We intend to do this indirectly, by studying adult mouse models that lack the TDP-43 protein. A relatively new technique lets us turn off the TDP-43 gene at will. So far, preliminary data suggests that in motor neurons, the TDP-43 protein, in turn, regulates a protein called SMN. (It’s of interest to know that loss of SMN causes Spinal Muscular Atrophy, a motor neuron disease that afflicts infants.)

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Yimin Zou, PhD

UCSD
Regeneration and Degeneration of Cortical Neurons

We study the basic mechanisms of how motor neurons are connected with muscle targets during normal development. Understanding the mechanism of motor axon outgrowth and guidance will potentially shed light of the cause of motor neuron degeneration. In the future, when stem cell techniques become available to help regenerate the impaired motor neurons, methods will need to be developed to guide these motor neuron axons to find their proper targets. Our studies will potentially provide such molecular tools to guide regenerating motor axons to reconnect to muscle targets to cure ALS patients.

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