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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 131 research grants and has several new grants pending, at a total of $25 million. The Center awards ALS research grants throughout the year on a flexible time frame, with the idea that rapid funding fosters innovative ideas. 

Barmada | Borchelt | Chen & Wong | Cleveland | Finkbeiner | Gao | Gitler & Shorter | Julien | Kabashi | La Spada | Landers & Gao | Lechtzin & Yuhas | Miller | MonteiroPandey | Petrucelli | RanumRobberecht | SattlerSockanathanSterneckertTaylor | WangWong | Wong | Xu

Sam Barmada, MD, PhD

University of Michigan
Mechanisms of initiation and progression in ALS

Funding for this project was made possible by The Boye Foundation

Motor neurons control all of our movements from walking to breathing. These cells are selectively hit early in ALS, but why motor neurons are so susceptible remains mysterious. Our goals are to (1) determine what makes motor neurons vulnerable in ALS, and (2) define how ALS spreads from neuron to neuron. With this knowledge, we will develop targeted treatments that prevent the death of motor neurons in ALS and prevent the spread of disease once it has begun.

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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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Liam Chen, MD, PhD & Philip Wong, PhD     

Johns Hopkins School of Medicine
Validation of a therapeutic target in TDP-43 animal models of ALS

This project is made possible through a collaboration with the Winokur Family Research Initiative and ALSA

How TDP-43, a protein associated with a vast majority of ALS cases, causes malfunction of nerve cells remains a mystery.  Depletion of this protein is thought to be responsible for killing nerve cells. We use mouse and fruit fly models that lack this TDP-43 protein to induce malfunction and death of nerve cells to help us identify drug targets for therapy.  We now identify a target called Atg7, a critical protein needed to breakdown unnecessary or dysfunctional components in nerve cells. To validate this target, we propose to use a series of tests in mouse and fruit fly models.  Specifically, we will test whether spermidine, a natural chemical compound produced in our body that stimulates production of this Atg7 protein, could provide benefit in our mouse and fruit fly models. Positive test outcomes from our proposal will allow us to validate this factor as a therapeutic target and hold promise for development of treatment strategies for 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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John Landers, PhD & Fen-Biao Gao, PhD    

University of Massachusetts
Modeling ALS-Associated Cytoskeletal Mutations in iPSC and Drosophila

The cytoskeleton is the scaffolding that helps the cell maintain its shape. Recently, we determined that mutations in two cytoskeletal proteins cause ALS. Here, we propose to introduce these mutations into induced pluripotent stem cell-derived human neurons and Drosophila to study how they contribute to the development of ALS.

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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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Mervyn J. Monteiro, PhD     

University of Maryland 
Generation and characterization of ubiquilin-2 transgenic mice models of ALS

Ubiquilin-2 mutations have been shown to cause ALS. To understand the molecular mechanisms by which the mutations cause disease we propose to generate and characterize transgenic mice carrying select human ubiquilin-2 mutations that we have found affect the synthesis, folding and degradation of proteins. The mice will be characterized using a battery of biochemical, pathological and behavioral examinations. Once developed these mice will provide useful models to test and validate candidate approaches to slow and/or halt 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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Leonard Petrucelli, PhD     

Mayo Clinic
The role of epigenetic changes and downstream pathological events in c9FTD/ALS

Funding for this project is made possible by Ann Arbor Active Against ALS (A2A3)

Amyotrophic lateral sclerosis (ALS) is an incurable disease of nerve cells that control muscles, and some patients with ALS have mental and behavioral abnormalities similar to frontotemporal dementia (FTD). We aim to discover the cellular disease processes initiated by mutations in the C9ORF72 gene in order to improve the diagnosis of and prognosis for patients suffering from disorders collectively referred to as c9FTD/ALS. By better understanding cellular disease processes known as epigenetic changes, we hope to identify new biomarkers and treatment therapies.

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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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Rita Sattler, PhD    

Johns Hopkins University
Role of synaptic dysfunction in C9orf72-mediated pathogenesis in patient-derived iPS neurons and in vivo animal models

Funding for this project is made possible by Ride For Life

The goal of this proposal is to study cellular and molecular mechanisms of disease pathogenesis induced by the novel C9orf72 mutation found to be highly prevalent in ALS patients. In specific, we aim to test the hypothesis that mutations in the C9orf72 gene lead to significant changes in the cellular structure of fine projections of neurons, so called axons and dendrites, which are important for the transmission of information from one cell to another. Preliminary data from our laboratory suggest that there is a structural rearrangement of the dendritic synapse, a specialized structure along those neuronal processes where cell to cell information exchange occurs, but also where memories are formed and lost, as is the case during cognitive impairment, which is frequently observed in C9orf72 ALS patients.

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Shan Sockanathan, PhD    

  Johns Hopkins University
Mechanisms of motor neuron loss in ALS

Our research focuses on identifying molecular pathways that are important for motor neuron survival, and determining if they are specifically impaired in ALS. These studies have the potential to discover relevant therapeutic targets to mitigate motor neuron loss in ALS and to identify biomarkers for this disease.

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Jared Sterneckert, PhD

Max Planck Institute for Molecular Biomedicine, Germany
Identification using HTS of small molecules protecting iPSC-derived MNs with mutant C9orf72 against degeneration

Funding for this project is made possible by Ann Arbor Active Against ALS (A2A3)

Patients with amyotrophic lateral sclerosis (ALS) become progressively paralyzed because their motor neurons (MNs) degenerate. Mutations in the gene C9orf72 are the most common known genetic cause of ALS. Reprogramming enables us to create stem cells directly from patients with mutations in C9orf72, which can be used to replay ALS pathology in a dish. Because it is stem cell-based, we can replay this model thousands of times and test new drug-like compounds for their ability to prevent ALS. As part of this project, we aim to test about 50,000 new drug-like compounds to identify new hit compounds, which, in the future, we hope to develop into new drugs that can prevent paralysis in patients with ALS.

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J. Paul Taylor, MD, PhD

St. Jude Children’s Research Hospital
Altered RNA Metabolism in C9ORF72-associated ALS

We generated and characterized a fruit fly model of C9ORF72-associated hexanucleotide repeat expansion. This model shows degeneration dependent on the number of GGGGCC-repeats, accumulation of expanded GGGGCC RNA and RAN translation, essentially providing a genetically tractable model of C9ALS/FTD.  We used this fly model to conduct an unbiased genetic screen that identified multiple RNA-binding proteins that regulate aspects of pre-mRNA splicing as strong genetic modifiers of this hexanucleotide repeat toxicity. This discovery strongly implies that accrual of GGGGCC RNA impairs key aspects of RNA metabolism. In this project we will test the hypothesis that certain specific aspects of pre-mRNA processing are impaired in C9ORF72-associated ALS.

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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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