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Packard Center for ALS Research at Johns Hopkins

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ALS Research Projects: Grants on the Rise

To date, the Robert Packard Center for ALS Research at Johns Hopkins has awarded 120 research grants and has several new grants pending, at a total cost of close to $24 million. The Center awards ALS research grants throughout the year on a flexible time frame, with the idea that rapid funding fosters innovative ideas. 

Borchelt | BrownCleveland | Finkbeiner | Gao | Gitler & Shorter | Julien | Kabashi | La SpadaLechtzin & Yuhas | Miller | Pandey | RanumRobberecht | Taylor | WangWong | Wong | Xu

David Borchelt, PhD

University of Florida
Propagation of toxic SOD1 conformations in ALS

 In many, if not most cases of ALS, the disease appears to spread along anatomically connected pathways. Whether this apparent spreading actually represents the physical spread of some entity that ultimately leads to loss of neuromuscular connectivity in life sustaining functions is presently unclear. We aim to investigate whether the spread of misfolded, toxic conformations of the superoxide dismutase 1 (SOD1) protein throughout the central nervous system has a role in the pathogenesis of ALS. We intend to use various techniques to first induce a focal accumulation of SOD1 and then determine whether these disease-specific proteins can propagate out from this point and spread within the spinal cord. These data will help to better understand the ALS disease process and may also have important therapeutic implications.

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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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Don Cleveland, PhD

Ludwig Institute for Cancer Research/UCSD
Mice expressing C9orf72 RNA for antisense oligonucleotide therapy development and decoding disease mechanism

Funding for this project was made possible through a collaboration between the Packard Center and ALSA

The most frequent cause of inherited ALS was discovered in October 2011 to be a large expansion of a hexanucleotide repeat in the C9ORF72 gene. When that large repeat is copied into the messenger RNA which carries the information encoded by the gene, the mRNA aberrantly accumulates. In other diseases caused by expanded repeats like myotonic dysrophy, factors required for processing the mRNA with the expansion – and needed for processing RNAs encoded by other genes – get trapped on the expanded repeat sequence, and correspondingly fail to mediate processing of the other RNAs. Building on that example and in partnership with Isis Pharmaceuticals, we have designed a gene silencing approach to develop a drug - called an antisense oligonucleotide or ASO - that will selectively destroy the ALS-causing mRNA with the expanded repeat. . We will build a mouse model expressing the expanded human C9ORF72 mRNA and use this to validate the efficacy of the ASO drug in development. The mice may also represent models that will develop ALS-like disease and which can be used to determine exactly what goes wrong in the presence of the aberrant mRNA.

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Steven Finkbeiner, MD, PhD      

Gladstone Institutes, UCSF
The Role of Nonsense-mediated Decay in ALS

Funding for this project is made possible by the William H. Adams Foundation

Two recently discovered genes that have been associated with both familial and sporadic forms of ALS encode the related proteins TDP43 and FUS. Our goal is to determine how TDP43 and FUS cause neuron death in ALS. Based on work in our lab and by other groups, we predict that mutant forms of TDP43 and FUS interfere with a cell’s ability to perform a quality control function called “nonsense mediated decay” which prevents the production of abnormal proteins in the cell. We have built a unique robotic microscopy time-lapse imaging system that allows us to test whether boosting the levels of an enzyme called UPF1 that performs this quality control can help neurons survive even in the presence of mutant or high levels of TDP43 and FUS. If so, we may be able to design drugs that increase or mimic UPF1 and prevent neurodegeneration.

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Fen-Biao Gao, PhD 

University of Massachusetts
Identification of Genetic Modifiers of GGGGCC Repeats Toxicity in Drosophila

A repeat expansion in the C9ORF72 gene is the most common causal mutation in amyotrophic lateral sclerosis and frontotemporal dementia. However, no one knows exactly how this mutation causes disease. We will use Drosophila as a model system to investigate neurotoxicity of these repeat expansions. We hope these studies will contribute to the development of potential therapeutic interventions.

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 Aaron Gitler, PhD & James Shorter, PhD   

Stanford University & University of Pennsylvania
Genetic and biochemical approaches to define mechanisms of RAN translation in C9orf72-associated ALS

Mutations in the C9orf72 gene are a common cause of ALS. New evidence points to a potential role for tiny peptides that are abnormally expressed from this gene and may contribute to the disease. In this project, the Gitler and Shorter labs will combine yeast experiments and biochemistry to identify the mechanisms by which these short peptides (produced through a mechanism known as Repeat Associated Non-ATG Translation Initiation) might cause disease. We also intend to develop strategies to help combat the formation of such peptides.

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Jean-Pierre Julien, PhD

Laval University, Quebec
Intrabody-based therapy to inhibit TDP-43 interaction with p65 NF-κB

We discovered that an upregulation of TDP-43 in ALS acts as co-activator of nuclear factor-κB (NF-κB) and that this interaction can induce hyperactivity of NF-κB resulting in exaggerated innate immune responses and increased neuronal vulnerability to toxic environment. Here we propose to develop a therapeutic approach based on expression of nuclear intrabodies (antibodies that work inside the cell) against TDP-43 to specifically block its interaction with NF-κB p65. We have generated a hybrid cell line that produces monoclonal antibodies against the RRM1 domain of TDP-43. From these cell lines, we will derive cDNAs encoding single chain antibodies (scFv) that will be used to generate an adeno-associated virus. This virus will encode intrabodies aiming to block TDP-43 interaction with p65 in the nucleus and to alleviate protein aggregation.

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Edor Kabashi, PhD

Brain and Spinal Cord Institute, Paris
Identifying molecular partners of mutant TDP-43 & FUS

Our goal is to identify novel protein partners of mutant TDP-43 and FUS that could contribute to mechanisms associated with motor neuron degeneration using the transgenic zebrafish models we previously developed. Identification of specific protein partners that can selectively induce neurodegeneration has been impeded by the similar toxic profiles of TDP-43 and FUS. The discovery of these partners can shed light to a better understanding of neurodegenerative pathways elicited in ALS and may provide both novel avenues for genetic factors in motor neuron diseases and new targets for therapeutic intervention in ALS patients.

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Albert La Spada, MD, PhD     

UC San Diego
Role of senataxin in regulating c9orf72 repeat mediated transcription dysregulation and neurotoxicity in ALS

Mutations in a gene known as senataxin cause a rare form of juvenile-onset ALS. The normal function of senataxin is to regulate how genes are turned into proteins by breaking up pieces of DNA and RNA that get stuck together during the process. Recent work on ALS has shown that the so-called “c9orf72” repeat expansions that cause ALS in human patients promote the formation of such RNA-DNA hybrids. Using a combination of approaches, including studying cell lines from human ALS patients and new mouse models of ALS disease mutations, we will determine if senataxin’s normal role is to regulate the formation of c9orf72 repeat-associated RNA-DNA hybrids and if an interaction between senataxin and the c9orf72 repeat expansion mutation is relevant to the onset and maintenance of ALS.

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 Noah Lechtzin, MD & Ben Yuhas, PhD

Johns Hopkins University
Improving the Accuracy of ALS Diagnosis in Medicare Claims to Better Detect Interactions Between Prescribed Drugs and Survival

In the first phase of this research, we demonstrated that Medicare claims data could be used to find interactions between prescribed drugs and the survival of beneficiaries with ALS. We were forced to use selection criteria that reduced our cohort of study from an initial population of 14,116 down to 744. Criteria were developed to handle those cases where we were unable to estimate disease onset and those cases where the ALS diagnosis was suspect. In this follow-up study, we intend to use time-series data to find alternative selection criteria that will allow us to recover many of our censored cases. By eliminating overly restrictive selection criteria we will broaden our ALS population of study and increase our cohort size.

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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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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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Laura Ranum, PhD     

University of Florida
Molecular Genetics of the G4C2 expansion mutation in ALS/FTD

This project is made possible through a collaboration with ALSA.

A novel form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) was recently shown to be caused by a DNA mutation in which six letters of the genetic code “GGGGCC” are repeated extra times. This discovery links ALS/FTD with a large group of other neurological diseases caused by similar repeat expansion mutations (e.g. CAG, CTG, CCTG), which is particularly exciting because lessons learned over the past 20 years from studying these other diseases are likely to be relevant to the more common ALS/FTD. My laboratory has followed a family with ALS for more than 20 years and recently discovered that this family has the GGGGCC expansion mutation. We have cloned the repeat expansion mutation from a member of this family and propose a series of experiments, including the generation of a mouse model to better understand how this expansion mutation causes disease.

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Wim Robberecht, MD, PhD

University of Leuven, Belgium
Role of Oligodendrocytes in the Pathogenesis of Mutant TDP-43 Associated ALS

Oligodendrocytes have recently been shown to contribute to the pathogenesis of ALS. TDP-43 plays a role both in familial and sporadic ALS. In this project, we intend to investigate whether expression of mutant or wild-type TDP-43 in oligodendrocytes or in oligodendrocyte precursor cells is sufficient to cause motor neuron degeneration. We also intend to compare the potential motor neuron degeneration in oligodendrocytes to the phenotype induced by selective expression of mutant or wild-type TDP-43 in motor neurons.

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J. Paul Taylor, MD, PhD

St. Jude Children's Research Hospital
The role of TDP-43 in RNA transport granules and the impact of disease mutations

Previous studies have shown that TDP-43 is part of the protein and nucleic acid complexes that transport molecules from the nucleus to the cytoplasm. Mutations to TDP-43 affect the cell's ability to move molecules into the cytoplasm. We hypothesize that these TDP-43 granules facilitate delivery and local translation of mRNAs in motor neurons. Specifically, we are studying the function of several proteins implicated in ALS (TDP-43, hnRNPA2B1 and hnRNPA1) that bind to mRNA immediately after it is transcribed by ribosomes. We intend to discover how these proteins are directly perturbed by disease mutation or indirectly impacted by mutations in VCP or C9orf72. This project is one of four thematically related projects investigating the role of perturbed RNA metabolism in ALS pathogenesis.

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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 University
Determining the pathogenic mechanism(s) of C9ORF72-linked ALS-FTD

Funding for this project was made possible through a collaboration between the Packard Center and ALSA; Packard Center funding made possible by A Midwinter Night's Dream

The hexanucleotide GGGGCC repeat expansion in a gene termed C9ORF72 is the major cause of ALS and FTD, but how such expansion causes malfunction of nerve cells in these illnesses remains unknown. We plan initially to develop mouse model systems to test if losing the activity of C9ORF72 is responsible for death of motor neurons and secondly, whether toxicity arises through the presence of a toxic RNA derived from the diseased C9ORF72 gene that determines malfunction of motor nerve cells. Outcomes from studies proposed in this application will clarify how the repeat expansion in the C9ORF72 gene causes motor nerve cell loss in a large proportion of cases of ALS. These efforts will have important implications for design of therapy and provide useful mouse model systems for testing therapies that would eventually benefit patients with ALS.

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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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Zuoshang Xu, PhD

University of Massachusetts
Modeling ALS by TDP-43 hypomorphism in mice

TDP-43 is a key causal gene that is involved in a majority of ALS cases, including the sporadic and some familial cases. To understand the role of TDP-43 in neurodegeneration and to design therapeutic strategies, a critical question to resolve is whether TDP-43 causes neurodegeneration by a gain of toxicity, e.g. from forming toxic protein aggregates, or from loss of its function, e.g. from mutations or being absorbed into the aggregates. To answer this question, both overexpression and loss-of-function models are necessary. This proposal will establish a transgenic mouse model for ALS by decreasing the level of TDP-43. This model will be important for understanding the disease mechanism and designing therapeutic strategies.

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Yongjie Yang, PhD

Tufts University
Role of Astrocyte Exocytosis in the Pathogenesis of ALS

This project aims to investigate the role of chemicals secreted by astrocytes in pathogenesis of motor neuron degeneration by employing novel mouse genetic tools. Results from this study will demonstrate whether these secreted compounds contribute to toxicity in astrocytes with a mutation in SOD1 and provide clues how to identify the toxic factors from astrocytes. Ultimately these results will help develop astrocyte-based neuroprotective strategies against motor neuron degeneration in ALS.

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