Projects

ALSFAC has contributed to major scientific progress in our understanding of the underlying biology behind ALS. As a direct result of the funded projects, research teams helped develop over 130 pre-clinical models and collect more than 4,440 patient medical records, and more than 8,300 samples. They also have helped identify 2 new ALS genes and validate one new ALS imaging biomarker. ​

PREVIOUS PROJECTS

Principal Investigator(s): 
Bob Brown, MD/DPhl
Justin Fallon, PhD
Anne Hart, PhD,
Diane Lipscombe, PhD
Robert Reenan, PhD
Brian Wainger, MD/PhD
Kristi Wharton, PhD

Collaborators involved: Leslie Thompson, PhD, Steve Finkbeiner, MD/PhD, Ernest Fraenkel, PhD, Jenny van Eyk, PhD

Brown University, University of Massachusetts and Massachusetts General Hospital

Overview and description:
The goal of the Accelerating ID Project is to identify the earliest detectable disease changes and to look for genes with the ability to suppress disease changes across 4 different animal and human-based models of ALS. This collaboration across 7 laboratories is specifically focused on:

  • Using unbiased screens to look for disease suppressors in worm and fly models of ALS
  • Performing sensitive new behavioral analyses in mice to detect early and subtle changes,
  • Exploring abnormal firing patterns in human stem cell-derived motor neurons from different genetic backgrounds
  • Disseminating the novel research tools that have been generated through the project

The labs have been generating novel genetic ALS models in flies and worms in order to look for disease suppressors across both models, and are now beginning to assess these suppressors in mouse and human-derived stem cells in hopes of identifying novel drug targets.

Web site:  Brown.edu

Principal Investigator(s): 
Katherine Nicholson MD
Nazem Atassi MD

Overview and description:
People with ALS often seek evaluation from multiple providers prior to diagnosis, with an average time from symptom onset to diagnosis of 11.5 months. The goal of this study is to accelerate ALS diagnosis by developing a natural language processing-based algorithm to identify people at risk for ALS and a scale to help physicians identify people with ALS at early stages of the disease. We aim to scale up these early ALS diagnostic tools for use in many US hospitals, with the ultimate goal to identify and treat people with ALS early in the disease when chances of drug success are higher. This project is co-funded by ALS Finding a Cure and Biogen.

Principal Investigator(s): 
Clive Svendsen PhD

Overview and description:
Induced pluripotent stem cell technology (iPSC) holds great promise for accelerating our understanding of the molecular mechanisms and pathways leading to motor neuron degeneration in ALS. In vitro cellular model systems generated from patient-derived iPSC lines can recapitulate many aspects of in vivo cellular pathology, and beyond basic disease research may serve as a powerful test bed to screen potential therapies. Therapeutic screening on iPSC-derived models will likely be complementary to, and in some aspects superior to other approaches, including animal models in terms of human-predictivity and speed. GE developed a unique technology platform allowing the in vitro analysis of cells and tissues to an extent not previously possible (MultiOmyx, or “MO”). An iterative labeling process allows repeated immunocytochemical visualization of 60 or more protein markers in a single sample, as well as RNA and DNA. Precision hardware and custom software for imaging and analytics enable extensive characterization of single cell structure and function as well as relationships with neighboring cells and environment. Application of this technology to ALS iPSC systems is likely to advance the utility of these models and provide new insights into neurodegenerative pathways and mechanisms.

Principal Investigator(s): 
Jeremy Shefner MD, Barrow Neurological Institute
Seward Rutkove, Harvard Medical School
Jeremy Shefner, Deaconess Medical Center

Collaborators involved: Barrows Neurological Institute, Beth Israel Deaconess Medical Center

Overview and description:
Only a small percentage of patients with ALS participate in clinical trials. A major reason is that trials are conducted in a limited number of academic medical centers, and that in-person visits are required on a frequent basis. At these visits, trial outcome measures are obtained, with trained evaluators performing these measures. Our study will test the hypothesis that ALS patients can perform clinically meaningful outcome assessments at home, thus obviating a major need to come to the study center. We will provide simple tools for assessment, train subjects via webinars, and patients will enter their data to an online portal. For a sample of participating patients, we will compare AT HOME measures with those obtained at regular study visits by trained evaluators. We will also assess the extent to which frequent sampling of measures can reduce the variability of measurement; we expect that such sampling will increase reliability of measurement and potentially reduce the sample size required to see meaningful changes in response to experimental therapies.

Web site:  ClinicalTrials.gov, Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS)

Principal Investigator(s):
Clive Svendsen
Gretchen Thomsen (Cedars Sinai)

Overview and description:
This study combined two exciting new areas in clinical development: Stem Cells and Gene therapy. Stem cells have the ability to divide and adapt to new environments. This project took advantage of these capabilities to transplant brain support cells that were genetically modified to express the growth factor GDNF. ALSFAC funded initial studies testing this approach in animals and the investigators then advanced to transplanting these cells into the spinal cords of ALS patients to assess their safety and whether they could promote any benefit/stabilization of disease.

Funding: $280,000

Web site:  https://www.cedars-sinai.org/newsroom/cedars-sinai-awarded-1199-million-for-als-clinical-trial/

Principal Investigator(s): 
Katharine Nicholson, MD
Tim Miller, MD/PhD
James Berry, MD

Collaborators involved:  Massachusetts General Hospital and Washington University

Overview and description:
DIALS was a multi-center initiative to follow pre-symptomatic ALS mutant gene carriers longitudinally in order to identify biomarkers at (or as close as possible to) the point of conversion to disease. The study not only used traditional clinical assessments, but also incorporated the novel strength measures ATLIS (measure of upper and lower limb strength) and the Iowa Oral Performance Instrument (IOPI) (a measurement of bulbar muscle strength) as well as the assessment of several potential fluid-based biomarkers. This project was originally funded to enroll 20 patients, but received additional funding from Target ALS to add another 40 patients, and Biogen to add an addition 25 patients.

Principal Investigator(s): 
Robert Brown D.Phil., MD

Collaborators involved:
Merit Cudkowicz MD, Massachusetts General Hospital
Clive Svendsen PhD, Cedars-Sinai Regenerative Medicine Institute
Robert Brown D.Phil., MD, University of Massachusetts Medical School

Overview and description:
The field of ALS needs a tool, often called a biomarker, by which the activity of this disease can be gauged. This is potentially important not only for diagnosing the disease, but also for identifying factors causing ALS and for gauging the efficacy of putative ALS treatments. One such biomarker is to quantify a parameter that directly reflects the health of the motor neuron. One property that is promising in this regard is axonal transport, the process by which a nerve cell moves cargoes such as proteins and organelles up and down its long processes known as axons. It is clear in ALS mice that as ALS progresses, axonal transport fails. There is no way yet to quantify rates of axonal transport in living mammals. The goal of this project is to use a non-toxic fragment of tetanus toxin to record rates of axonal transport in human motor nerves. Our group has long-standing experience studying this fragment of tetanus (called TTC) for this purpose. In the present study, we will test ways to label TTC so that we can visualize and quantify its movement using either MRI scans or a method called PET scanning.

Impact of Study
We believe this study can potentially have a high impact. This is in part because of the urgent need for a quantitative biomarker in ALS. It is also because a measure of axonal transport should be useful in many other disorders of the motor nerve, including motor neuropathies, some types of muscular dystrophy, and traumatic nerve injury.

Common Goals
Finding a common biomarker is a goal shared by many ALS investigators, including others in the ALS Finding A Cure Foundation. In this regard, our work dovetails well with the studies in this consortium using PET ligands to visual neuroinflammation. Moreover, these biomarkers should prove useful in gauging success of any ALS treatment trials that emerge from this consortium.

Principal Investigator(s): 
Katharine Nicholson MD
James Berry

Collaborators involved: Massachusetts General Hospital, Harvard School of Public Health, The Broad Institute

Overview and description:
There is growing interest in how the interplay between the intestinal microbiota (i.e., bacteria in the gut) and its host influence the onset and course of neurodegenerative diseases, potentially mediated by immune mechanisms that modulate the microglial environment. No studies have previously examined whether the overall composition of the intestinal microbiota, or specific bacterial species, are associated with ALS. In this pilot study, the intestinal microbiota of 100 people with ALS and 100 healthy controls was compared. The study used novel technology and was a collaboration project among the Harvard School of Public Health, Broad Institute, and the Neurological Clinical Research Institute at Massachusetts General Hospital, involving leading epidemiologists, microbiome analysts, and ALS clinical researchers.

Principal Investigator(s): 
Merit Cudkowicz MD, Massachusetts General Hospital
Nazem Atassi, Ph.D., University of Massachusetts in Worcester, Mass
James Berry MD, Massachusetts General Hospital
James Berry, MD, Massachusetts General Hospital

Overview and description:
The NEALS Biorepository project encompassed three sub-projects: 1) NEALS Biorepository Infrastructure Improvements, 2) Cross-Sectional ALS Biofluid Biomarker (CABB) Study, and 3) Longitudinal ALS Biofluid Biomarker (LABB) Study.

The Biorepository Infrastructure Improvements included procedural, physical, and information technology improvements to the NEALS Biorepository to improve sample security, encourage sharing, and reduce turnaround time.  The infrastructure improvements enabled the distribution of over 4300 vials of biofluids over the course of the project.

The CABB Study was a new study conducted at multiple NEALS clinical sites to collect blood, DNA, and clinical information from a large group of people with ALS to expand the biorepository.

The LABB Study was a study aimed at collecting blood, DNA, RNA, spinal fluid, and clinical information from patients every four months over the course of their disease, as this type of longitudinal sample collection plus clinical data is enormously helpful for biomarker and diagnostic identification.

Funding:  ALSFAC and the ALS Association

Web site: Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS)

Principal Investigator(s): 
Meric Cudkowicz MD, Massachusetts General Hospital
Alex Sherman, Massachusetts General Hospital

Collaborators involved:

Overview and description:
NeuroBANK™ is a patient-centric clinical research platform that allows for the capture and aggregation of clinical and clinical research data from simultaneously-running research projects and the linking of these data with biospecimen repositories, image banks and genetic information. Embedded Global Unique patient Identifier (GUID) technology allows for the generation of patient-specific ID’s that uniquely and securely identify a patient without a risk of exposure of that patient’s true identity. Unlike any other existing platform for ALS clinical research, NeuroBANK™ makes it possible for the information captured from a patient participating in multiple clinical studies to be captured and linked within in a single system, thus enabling a deeper assessment of patient data.

The development of NeuroBANK™ allows for a standardized patient-centric approach to clinical research in ALS with information linked across studies, locations and modalities. Standard Common Data Elements, standard operating procedures and GUID technology enables accelerated study review, approval, deployment, and patient enrollment, as well as improving the ALS clinical research community’s ability to leverage precious clinical data.

Funding:  ALSFAC and the ALS Association

Papers summarizing results and findings:

Web site: neurobank.org

Principal Investigator(s): 
Joshua Cohen, Amylyx Pharmaceuticals
Justin Klee, Amylyx Pharmaceuticals

Collaborators involved:
Shayne Gad PhD, Gad Consulting Services
Dexter Sullivan MS, Gad Consulting Services

Overview and description:
Neurodegeneration and neurotoxic inflammation are hallmarks of ALS and together form a vicious cycle that is one of the key drivers of functional decline in patients. Our lead candidate, AMX0035, is a proprietary combination of two compounds that is designed to break this cycle, thereby halting clinical progression. Based on strong in-vitro and in-vivo results, we now seek to evaluate our promising therapeutic in patients with ALS.

Nonclinical safety studies, also called toxicology studies, are the essential FDA-required battery of tests needed to translate a therapy from the lab to the clinic. We met with the FDA in a pre-IND meeting and received consent that our safety program would be sufficient to support our first clinical trial. As of September 16, 2015, we are approximately halfway through these safety studies, and have completed:

1) The Ames Test

2) Evaluation of Maximum Tolerated Dose in Rat and Mini-pig

3) Dose Range Finding in Rat (mini-pig is currently underway)

4) Development of Bioanalytical Methods

Following completion of our nonclinical safety program in early 2016, we will file an IND with the FDA to run a first-in-human clinical trial. We are very grateful to ALS Finding a Cure for their support for these pivotal studies that will bring AMX0035 to patients in need.

Web site: http://www.fiercebiotech.com/biotech/als-upstart-amylyx-gains-3m-grant-to-start-combo-trial

http://www.prnewswire.com/news-releases/the-als-association-and-als-finding-a-cure-announce-joint-funding-support-for-amylyx-clinical-trial-of-amx0035-for-the-treatment-of-als-300300955.html

http://www.businesswire.com/news/home/20160822005017/en/Amylyx-Announces-5-Million-Series-Financing-Support

Principal Investigator(s): 
Jeff Rothstein (JHU)
Clotilde Lagier-Tourenne (MGH)

Overview and description:
To investigate the biology of nuclear pore dysfunction in autopsied brain tissue from ALS patients, stem cells derived from ALS patients, and within new rodent models, and ultimately to use these tools to probe new candidate therapies targeting nucleocytoplasmic transport.

Funding: $230,000

Principal Investigator(s): 
Nazem Atassi MD, Massachusetts General Hospital

Overview and description:
The goal of this project is to measure spinal cord inflammation using [11C]PBR28-PET in 10 people with ALS compared to 5 healthy volunteers. Positron emission tomography (PET) is a technology that allows accurate measurement of certain proteins or metabolites in living people. We are using a PET tracer (contrast) called PBR28 that binds to active inflammatory cells and allows us to measure and localize brain inflammation. We were able to demonstrate increased inflammation in the areas that control voluntary muscle movements (e.g., motor cortex) in people with ALS. Zucher N, Lawson R, Loggia M, Chonde DB, Izquierdo D, Akeju O, Catana C, Rosen B, Cudkowicz ME, Hooker J, Atassi N. Microglial Activation in Individuals with Amyotrophic Lateral Sclerosis. Neuroimage Clin 2015 (PMC 25685708)

Impact of Study
The SPINE ALS project will build on our previous findings in the brain and demonstrate feasibility and relevance of imaging spinal cord inflammation as a molecular biomarker of lower motor neuron degeneration in people with ALS. A positive signal in this pilot study will provide the needed data to scale up and conduct a larger multi-center study in collaboration with General Electric (GE) using GE-180. This would nicely dovetail the ongoing TRACK ALS project and leverage the exciting collaboration between these sites and GE.

Overview and description:
A collaborative project with Target ALS, launched in 2016-7 to co-fund 5 academic-industry consortia on the following topics

  1. Project to optimize drug-like properties of a drug company’s proprietary compounds that rescue TDP43, FUS, and C9orf72-derived di-peptide repeat toxicity in yeast, neurons, C. Elegans, and human iPSCs
  2. Project to identify small molecules that inhibit the formation or accelerate the resolution of stress granules using patient derived iPSCs and determine their effects on neuronal viability and then use these to identify potential lead compounds with drug-like properties
  3. To develop robust preclinical data supporting an inhibitor of nucleocytoplasmic transport in order to advance to Phase I/II clinical trial
  4. To develop a gene therapy approach targeting non-sense mediated decay as a therapy against TDP43 and FUS-mediated toxicity
  5. Developing human antibodies against di-peptide repeats as a therapeutic approach to C9 ALS

Funding: $900,000

Web site: https://www.targetals.org/research/funded-consortia

Principal Investigator(s): 
Nazem Atassi MD,
Joseph Masdeu, MD, PHD
A. Nadeem Ishaque PhD
Suma Babu, MGH

Investigator(s): 
A. Nadeem Ishaque PhD, Vladimir Reiser PhD, Luca Marinelli PhD, Merit Cudkowicz MD, Nazem Atassi MD, Stanley Appel MD, Joseph Masdeu MD, PHD, Clive Svendsen PhD

Collaborators involved:  The Methodist Hospital Research Institute, Massachusetts General Hospital, GE, and Cedars-Sinai Medical Center, ALS Association

Overview and description:
The overall goal of this project is to identify new imaging markers of ALS that can be used to accelerate ALS diagnostic timelines and the pace of ALS drug development.

The study is focused on comparing MRI signals between 50 people with ALS and 50 healthy volunteers, and to study these MRI signals over time in relationship with ALS clinical presentation, disease progression, and comprehensive biomarkers profiling including DNA, IPSC lines and inflammatory blood-based markers.  A subset of these patients are also undergoing positron emission tomography (PET) to show the location and degree of brain inflammation in people with ALS. Lastly, a related study (SPINE ALS) uses MRI and PET technology to explore the ability to detect signals in the spinal cord of ALS patients. These studies leverage GE Healthcare’s work in TBI and bring GE’s imaging expertise to a study in ALS.

Web site: ClinicalTrials.gov

Principal Investigator(s): 
Gretchen Thomsen, PhD, Cedars-Sinai Medical Center
Eric Ley, MD, Cedars-Sinai Medical Center

Collaborators involved:  Robert Baloh, MD/PhD, Cedars-Sinai Medical Center

Overview and description:
The hypothesis behind this study was that the brain plays a critical role in ALS disease onset and therefore if one could prevent brain cell death this could delay disease onset and enhance survival of spinal motor neurons. This hypothesis was tested through a series of experiments in both SOD1G93A rat and C9orf72 mouse models. The study found that administering a controlled chronic traumatic brain injury did exacerbate disease progression and decrease time to disease onset in the rat SOD1 ALS model, however an acute TBI did not exacerbate death. The C9orf72 studies are ongoing under a no-cost extension.

Principal Investigator(s): 
Tim Miller (WashU)

Collaborators involved:
NIH also co-funded this study

Overview and description:
Novel therapies are being developed for Amyotrophic Lateral Sclerosis (ALS) caused by changes in the gene superoxide dismutase 1 (SOD1). This study assessed how quickly SOD1 protein was normally cleared from the cerebrospinal fluid (CSF) that bathes the brain and spinal cord in humans. These data helped determine the optimal time to administer drugs targeting SOD1, including the ALSFAC-funded study of AAV10 SOD1 silencing, and also Biogen’s Tofersen study.

Funding: $260,000

Web site: https://clinicaltrials.gov/ct2/show/NCT03449212?term=SOD1+Kinetics&draw=2&rank=1

Principal Investigator(s): 
Tim Miller, Washington University
Noah Zaitlen, UCSF
Shan Sockanathan, Johns Hopkins

Overview and description:
The exact cause of amyotrophic lateral sclerosis remains unknown, and there are no tests to diagnose the disease or follow its progression. Such tests, known as biomarkers, would be invaluable to speed the development of novel therapies for ALS. In recent years, ALS scientists have begun to identify promising potential biomarkers in the blood and spinal fluid of people with the disease. The next step to build on these discoveries, in many cases, is to test larger numbers of biofluid samples to confirm the findings. Therefore, a multi-foundation collaboration spearheaded by the ALS Association issued a global call for letters of intent from academia and pharma for ideas of ways to identify and/or validate ALS biomarkers, building on our investment in developing a large repository of well annotated, quality controlled cross-sectional and longitudinally collected biosamples. ALS Finding a Cure funded 3 biomarker projects at UCSF, Johns Hopkins, and Washington University through this collaborative mechanism.

Funding:  The ALS Association and ALSFAC

Web site: Biomarkers | The ALS Association, ALS Accelerated Therapeutics (ALS ACT) | The ALS Association

ACTIVE PROJECTS

Principal Investigator(s): 
Jeff Rothstein
Merit Cudkowicz
Clive Svendsen

Collaborators involved: Leslie Thompson, PhD, Steve Finkbeiner, MD/PhD, Ernest Fraenkel, PhD, Jenny van Eyk, PhD

Overview and description:
The Answer ALS project has four components:

  1. To collect 1000 ALS patient’s clinical data and biosamples

a) Including biofluids, tissue, blood, autopsy, DNA, PBMC’s, and

b) Digital data from smart phone-based applications

  1. To generate stem cells from every patient
  2. To use these stem cells to perform comprehensive biological analytics (generating extensive data on each patient)
  3. To analyze these data and make the data widely available to the community

The ultimate goal of the Answer ALS initiative is to be able to identify distinct disease subpopulations to better enable future precision medicine approaches and designer drugs.

Funding:  ALSFAC, Packard Center, the ALS Association, and others

Web site: Answer ALS – Answer ALS

Principal Investigator(s): 
Yuna Ayala
Nigel Cairns
Paul Kotzbauer
Vijay Sharma
Tim Miller

Overview and description:
TDP43 is the dominant neuropathology in ALS, found in 97% of brains studied during autopsies. This project, the winner of a $1M Challenge collaboratively funded by the ALS Association and ALSFAC, is focused on developing a PET imaging agent that binds selectively to abnormally aggregated TDP43, for use in imaging patients with suspected or diagnosed ALS. Such an imaging agent would be a powerful tool for use in both ALS clinical trials, as well as diagnosis.

Funding:  ALSFAC, the ALS Association, and the Association for Frontotemporal Degeneration