The ALS Association Announces New Research Grants

The ALS Association’s TREAT ALS (Translational Research Advancing Therapies for ALS) Portfolio is a research endeavor enabling important global research to progress from the laboratory to the bedside. The focus of the program is to support novel ideas, build tools, partner with academia and industry to identify new potential therapies, and support the infrastructure for clinical trials with the goal to find meaningful treatments and a cure for ALS. The Association is pleased to announce seven new grants. These grants focus on understanding disease mechanisms, the development of induced pluripotent stem cell lines as model systems to test compounds, the development of mouse models, and approaches to treating the disease linked to the recently identified mutation C9orf72.

Establishing Whether SOD1 Drives Astrocyte-Mediated Motor Neuron Toxicity in Sporadic ALS

Don Cleveland, Ph.D. Ludwig Institute for Cancer Research, University of California, San Diego, California

Damage accumulated within astrocytes, crucial partner cells for motor neurons, has been linked to many instances of sporadic ALS. Recent evidence has linked a specific protein produced by astrocytes, superoxide dismutase (SOD1), to the astrocyte-derived toxicity to motor neurons. By examining a collection of extraordinarily well preserved tissue samples from sporadic ALS patients, investigators will determine if SOD1 accumulates aberrantly in sporadic ALS similarly to what has been previously proven to be the case in inherited ALS caused by mutation in the gene encoding SOD1. By using astrocytes produced from stem cells from sporadic ALS patients that can become motor neurons or astrocytes, they will test the very provocative proposal that astrocytes from sporadic ALS patients are toxic to motor neurons and that toxicity requires SOD1. If this proves to be true, this will have important –and immediate— implications for therapy development in sporadic ALS: it will enable the expansion of ongoing therapy efforts, including a gene silencing trial for inherited ALS caused by mutation in SOD1, as appropriate therapies for sporadic ALS.

Genomic Studies for ALS

Richard Myers, Ph.D. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama

Funded by the Alabama Chapter of The ALS Association

To date, several genes have been identified where mutations in them result in the disease. Researchers have generated mice that have symptoms and progression of the disease by inserting and over expressing mutant versions of the human gene. We will use one of the mouse models to help understand the molecular mechanisms that result in ALS. Our plan is to apply state-of-the-art cell isolation and high-throughput DNA sequencing technologies to identify changes in the readout of all genes (by measuring the "transcriptome," or all messenger RNAs, in the cells) in the mouse model that result from having a mutant versus a normal gene.

Computational Dissection of Motor Neuron-Glial Interactions

Tom Maniatis, Ph.D. Columbia University, New York City, New York

Funded by the Greater New York Chapter of The ALS Association

The fundamental causes underlying the selective death of motor neurons, and the role that neighboring glial cells play in influencing motor neuron survival, are currently under intense investigation. To understand how intrinsic and extrinsic factors combine to influence motor neuron survival, the different cell types must be studied both in isolation as well as together. To study the causes and progression of ALS, and how changes in different types of glia affect motor neurons, investigators have collected sequencing data from isolated mutant and wild-type glial and neuronal cells over a time-course in vitro; in addition, they have also collected a longitudinal series of microglial cells from an SOD1-based mouse model of ALS in vivo. The investigators aim to collect similar longitudinal samples of astrocytes and oligodendrocytes from the same SOD1-based mouse model. Using state of the art technologies in collaboration with Richard Myers, Ph.D. at the HudsonAlpha Institute for Biotechnology, they will profile all the gene changes. The investigators will computationally mine these expression profiles for insights into the interactions between motor neurons and glia and how they are involved in disease.

Tracking Methods for Stem Cells in Human Clinical Trials

Thais Federici, Ph.D. Emory University, Atlanta, Georgia

Clinical trials using stem cells to treat ALS have been promising. However, most of these trials lack an approach for tracking the cells. This has made it difficult to understand what happens to the stem cells after they are transplanted into the patient. We propose to label the cells with particles that allow us to see them with magnetic resonance imaging (MRI) while the patient is still alive and to identify them in tissue samples. In order to use these particles in patients, they must first be validated in cells and animals. While these particles have been used in patients previously, many questions remain unanswered about their effect on stem cell function, safety in patients, and usefulness in tracking cells. The labeled cells will be tested for function in cells, rodents and pigs. We will assess the ability of the labeled cells to be visualized in the animals with MRI and to be identified in tissue samples. Furthermore, using a rodent with ALS, we will assess the effect the label has on the efficacy of stem cell therapy.

Modeling ALS/FTD in Mice by Inducible Knockdown of TDP-43

Zuoshang Xu, Ph.D. University of Massachusetts, Worcester, Massachusetts

Mutations in the TDP-43 gene cause ALS, and wild type TDP-43 forms intracellular protein aggregates in both sporadic and familial ALS and frontotemporal dementia (FTD). TDP-43 may cause the diseases by a gain of toxicity, whereby TDP-43 acquires a new property that is not part of the normal TDP-43 function and is toxic to neurons. Alternatively, TDP-43 may cause the diseases by a loss of its function, meaning that TDP-43 function is compromised either by genetic polymorphism or by environmental factors. Whether a gain of toxicity or a loss of function is the mechanism has not been settled but is crucial for the future of research on these diseases and the design of therapeutic strategy. To resolve this issue, investigators have taken a unique approach by modeling a partial loss of TDP-43 function using transgenic RNAi in mice. Their preliminary studies have demonstrated that a partial loss of function caused phenotypes typical of ALS and FTD in mice, thus suggesting that a loss of TDP-43 function causes these diseases. This proposal will focus on improving this model system to conceptually prove that a partial loss of TDP-43 function can cause ALS and FTD, and in the meantime, providing the research community with a highly flexible in-vivo model for future studies of these diseases.

Therapy Development for C9orf72 Related Disease: An Antisense Oligonucleotide-Based Approach

Michael Benatar, M.D. Zane Zeier, Ph.D., Claes Wahlestedt, M.D., Ph.D., University of Miami Miller School of Medicine, Miami, Florida

The recent discovery that a repeat expansion in the C9ORF72 gene may cause both ALS and FTD is very significant for a number of reasons. Not only is this genetic mutation the most common cause of both apparently sporadic and familial ALS, but the nature (i.e. repeat expansion) and location (i.e. non-coding region of DNA) of the genetic abnormality strongly suggest that it exerts its effect via an effect on the processing and metabolism of RNA. Moreover, the nature of the genetic abnormality is such that it lends itself to therapeutic intervention using a type of gene therapy known as anti-sense oligonucleotides. In the current study, investigators propose a strategy to (a) refine our understanding of the relationship between the genetic abnormality and the clinical presentation; (b) develop a semi-high-throughput method for screening potential treatments; and (c) complete an initial screen of a panel of antisense oligonucleotides designed to target the C9ORF72 gene. This study aims to complete the early steps needed to develop gene therapy for a subgroup of patients with ALS ± FTD.

Amyotrophic Lateral Sclerosis Induced Pluripotent Stem Cell Consortium

Funded by the Greater Philadelphia Chapter of The ALS Association

The ALS Association partners with the National Institute of Neurological Disorders and Stroke (NINDS) to continue the support of the ALS iPSC Consortium. The ALS Consortium is directed by Dr. Jeffrey Rothstein, Johns Hopkins University, and includes three principal investigators, working in tight collaboration, to generate and evaluate familial ALS (fALS) iPSC lines. The principal investigators include Drs. Kevin Eggan (Harvard University), Chris Henderson (Columbia University), and Merit Cudkowicz (Massachusetts General Hospital) .To generate iPSC lines, this consortium subcontracted with iPierian, a San Francisco-based biopharmaceutical company. The consortium is currently using the iPSC lines to determine molecular, biochemical and electrophysioloigcal phenotypes associated with the various mutations in both iPSC-derived motor neuron and astrocyte cultures. The cell lines are available for investigators world-wide from Coriell http://ccr.coriell.org/Sections/Search/Search.aspx?PgId=165&q=induced+pluripotent+stem+cells.