Funded Consortia

A Snapshot of Our Innovative Research Consortia

Target ALS-funded collaborative consortia are at the forefront of driving discovery, validation, and development of new ALS drug targets and clinical biomarkers. Here is a brief overview of our funded consortia.

2020
$15 Million Initiative Includes Launch of Newly Funded Projects Targeting Biomarker Discovery and Development

In December 2020, four projects were selected to receive funding based on their potential to advance ALS biomarker discovery and development. These grants were awarded as part of the new Target ALS Diagnosis Initiative, a $15 million comprehensive effort to discover ALS biomarkers, which Target ALS announced in November 2020. This overall research initiative is the first of its kind — developed in response to the input of over 100 scientists and other thought leaders, who universally reinforced ALS biomarkers as a critical unmet need to diagnose the disease early, track its progression and provide reliable measures for new treatments.

 

  • AC Immune’s high-sensitivity biofluid assays for detection of TDP-43 as an ALS biomarker
    Ruth Luthi-Carter (AC Immune), Ghazaleh Sadri-Vakili, Clotilde Lagier-Tourenne, Steven Arnold and James Berry (Massachusetts General Hospital)
  • Identification of novel biomarkers for TDP-43-associated protein expression and signaling in longitudinal CSF samples
    Yi Chen (Biogen), Jiou Wang and Phil Wong (Johns Hopkins University)
  • Neuron-derived exosomes as a biomarker platform for Amyotrophic lateral sclerosis
    Erez Eitan (NeuroDex Inc.), Sabrina Paganoni (Massachusetts General Hospital), Jeff Rothstein (Johns Hopkins University)
  • Characterization of Neurofilament light chain isoforms and post-translational modifications in blood and CSF of ALS patients using mass spectrometry
    Toby Ferguson (Biogen), Tim Miller and Cindy Ly (Washington University), Randall Bateman (Washington University)

2020
$5 Million in Grants Announced Targeting Treatments and Biomarkers for Both ALS and FTD

In 2020, Target ALS and The Association for Frontotemporal Degeneration (AFTD) announced $5 million in funding awards for work by six research teams to aid in the discovery of biomarkers and viable treatments for ALS and frontotemporal degeneration (FTD). ALS and FTD, the most common dementia under 60, overlap in genetic causes and biological mechanisms. These newly funded projects will inform, and potentially result in, both viable treatments and the biomarkers critically needed to enable accurate diagnosis and measure disease progression. The six collaborative projects will assess promising potential ways to detect—and therapeutic strategies to address—ALS/FTD pathology.

 

  • Mechanistic validation of HDAC6 inhibitors as a disease-modifying therapeutic for ALS and FTD
    Janice Kranz (Eikonizo Therapeutics), Ludo Van Den Bosch (VIB-KU Leuven), Yongjie Zhang (Mayo Clinic), Koen Van Laere (UZ/KU Leuven)
  • Targeting G3BP1 and the stress granule response as a therapy for ALS & FTD
    Dominique Cheneval (Novation Pharmaceuticals, Inc.), Christine Vande Velde and Alex Parker (Université de Montréal/CRCHUM)
  • Small Molecules Interacting with RNA (SMiRNA™) as a Therapeutic Strategy for C9ALS/FTD
    Sai Velapaudi (Expansion Therapeutics), Matt Disney (Scripps Research Institute)
  • Small Molecule Screen to Identify Selective Inhibitors of Aberrant TDP-43 Biocondensates in a Disease-Relevant Model
    Sophie Parmentier Batteur and Shahriar Niroomand (Merck & Co.), Jim Shorter (University of Pennsylvania), Chris Donnelley (University of Pittsburgh)
  • Antisense Oligonucleotides to Restore Expression of Full Length Stathmin 2 in Sporadic ALS
    Daniel Elbaum (QurAlis), Kevin Eggan (Harvard University), Bob Brown and Jonathan Watts (University of Massachusetts Medical School)
  • Poly(GR) and poly(GA) as Biomarkers and Therapeutic Targets in C9ORF72-ALS/FTD
    Mark Kankel (Biogen), Fen-Biao Gao (University of Massachusetts Medical School), Sami Barmada (University of Michigan Medical School)

2019
Successful Industry and Young Investigator-Led Consortia Receive Year Three Funding

In January 2019, the Target ALS Independent Review Committee (IRC) granted six of the most promising collaborative projects from the 2016/17 industry and young investigator funding calls an additional year of funding.

  • Targeting Stress Granule Dynamics for Familial and Sporadic ALS: Joe Lewcock (Denali Therapeutics, Project Leader), Gene Yeo (University of California, San Diego), Steve Finkbeiner (Gladstone Institutes).
  • Developing human-derived antibodies to target dipeptide-repeat protein toxicity in C9ORF72 disease: Fabio Montrasio (Neurimmune, Project Leader) Laura Ranum (University of Florida), Magdalini Polymenidou (University of Zurich), Clotilde Lagier-Tourenne (Massachusetts General Hospital).
  • Nuclear Export Inhibitor KPT-350 for C9orf72 and Sporadic ALS: Alex McCampbell (Biogen, Co-Project Leader), Jeff Rothstein (Johns Hopkins University, Co-Project Leader), Thomas Lloyd (Johns Hopkins University), Laura Ranum (University of Florida).
  • Exploiting yeast to discover small-molecule drugs for ALS caused by aberrant TDP-43, FUS, and c9orf72 dipeptide repeat protein homeostasis: Dean Brown & Nick Brandon (AstraZeneca, Co-Project Leaders), Jim Shorter (University of Pennsylvania), Steve Finkbeiner (Gladstone Institutes), Aaron Gitler (Stanford University).
  • Identification of RAN Translation Regulators as Therapeutic Targets in C9ORF72-Related ALS: Shuying Sun (Johns Hopkins University, Project Leader), Michael Bassik (Stanford University), Aaron Gitler (Stanford University), Fen-Biao Gao (University of Massachusetts), Joel Richter (University of Massachusetts).
  • Spatially resolved transcriptome wide analysis of gene expression in the spinal cord in ALS: Hemali Phatnani (New York Genome Center), Joakim Lundeberg (KTH Royal Institute), Richard Bonneau (New York University).

2018
Landmark, Precompetitive Biomarker Initiative Launched

  • The ability to diagnose ALS early, track disease progression, or to group patients with similar forms of the disease requires reliable biomarkers. The barriers to discovery and development of biomarkers are especially intractable due to the higher costs, difficulty in accessing optimal biospecimens, and requirement of multi-disciplinary expertise. To address these challenges, Target ALS launched a precompetitive biomarker initiative that connects pharma/biotech industry, academic experts, and foundations to collaboratively discover and develop new biomarkers for ALS.

 

Validation of Neurofilament Light Chain (NfL) and Neurofilament Heavy chain (NfH) in longitudinal CSF samples

  • This study was co-funded by Target ALS and The Muscular Dystrophy Association (MDA). Both neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), in blood and CSF, have been proposed to have potential as diagnostic, prognostic and pharmacodynamic biomarkers for ALS. The efforts prior to this study to evaluate NfL and pNfH as prognostic biomarkers for ALS have been hampered by access to small number of samples, lack of comparison across assay platforms as well as access to well characterized biospecimens. The samples used in this study were collected through a prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11). The samples were blinded, and the assays performed by independent contract research organizations.
  •  The results of this study, published in the journal Neurology, revealed that serum NfL may be considered a clinically validated prognostic biomarker for ALS. The study also opined that serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

 

Validation of longitudinal urinary p75 neurotrophin receptor extracellular domain (p75ECD)

  • This study was co-funded by Target ALS and MDA. The analysis of urinary samples is ongoing. We anticipate results to be available by Q1, 2021.

 

TDP-43 Biomarker Development

  • TDP-43 pathology is the most common neuropathologic hallmark in ALS, occurring in greater than 90% of all cases. TDP-43 pathology is also a common neuropathologic feature in other neurodegenerative diseases, including FTD and AD. However, detection of pathologic forms of TDP-43 are currently limited to post-mortem tissues. We lack the ability to accurately measure and monitor TDP-43 in living subjects, limiting our ability to use TDP-43 as a biomarker of disease. A number of commercial ELISA based immunoassays for TDP-43 currently exist, though the literature has generated conflicting results using these assays with respect to the reported levels of TDP-43 in the CSF or blood of ALS patients. Therefore, development of improved assays that can accurately measure and quantify TDP-43 in human biofluids would have tremendous impact on clinical research and therapeutic development for ALS and other neurodegenerative diseases.

 

TDP-43 Assay Development

  • A group of antibodies sourced from commercial, academic and industry partners are being used to create new TDP-43 immunoassays on the Meso Scale Discovery (MSD) platform to measure forms of TDP-43 in the CSF and blood of ALS patients. As a source of TDP-43, we have obtained purified protein expressed from cultured cells, as well as brain tissue extracts from patients with or without known TDP-43 pathology. Different combinations of capture and detection antibodies are being tested to identify the optimal antibody pair that recognizes different species of TDP-43 in CSF or blood of ALS patients when compared to healthy controls.

 

Mass Spectrometry to Determine TDP-43 species in Biofluids

  • A second project is using unbiased mass spectrometry to identify TDP-43 peptides species present in biofluids of patients with ALS, when compared to healthy controls. This project is utilizing CSF and blood from ALS patients known to contain TDP-43 pathology to determine what forms of TDP-43 are present in the CSF and blood. This project will shed important and novel insights into pathologic species of TDP-43 present in ALS biofluids, which may include altered TDP-43 truncations, novel post-translational modifications or fibril species. This information will ultimately be fed back into the initial project to develop additional and novel immunoassays for pathologic species of TDP-43 as well as to inform creation of new TDP-43 based animal models and potentially neuroimaging strategies.

 

2016 – 2017
Consortia Funded to Examine Disease Mechanisms, Targets, and Biomarkers

Target ALS sought to build on the momentum generated by earlier funding calls by supporting multi-disciplinary teams who were working on ALS research themes, targets, or biomarkers.

  • Validating poly(GP) and pNFH as biomarkers to detect symptomatic conversion in c9ALS: Leonard Petrucelli (Mayo Clinic, Project Leader), Tania Gendron (Mayo Clinic), Andreas Jeromin (Iron Horse Diagnostics), Yongjie Zhang (Mayo Clinic), Michael Benatar (University of Miami), Katharine Nicholson (MGH), Nathan Staff (Mayo Clinic), Alex McCampbell (Biogen).
  • Regulatory and Therapeutic role of microRNAs in ALS: Samuel Pfaff (Salk Institute for Biological Studies, Project Leader), Eran Hornstein (The Weizmann Institute), John Ravits (University of California, San Diego).
  • Therapeutic potential of CRISPR-Cas9 in C90RF72 – repeat deletion and transcriptional repression strategies in C90RF72 BAC transgenic mice: Laura Ranum (University of Florida, Project Leader), Eric Wang (University of Florida), Chad Cowan (CRISPR Therapeutics).
  • Mechanisms of cortical hyperexcitability in ALS: Solange Brown (Johns Hopkins University, Co-Project Leader), Clifford Woolf (Children’s Hospital Boston, Co-Project Leader), Paola Arlotta (Harvard University), Dwight Bergles (Johns Hopkins University), Loyal Goff (Johns Hopkins University).

Ground-breaking Industry-led Consortia Focused on Candidate Therapeutic Targets and Disease Mechanisms

For the first time in the history of ALS research and in partnership with ALS Finding a Cure, Target ALS designed its 2016 ALS funding call to encourage ALS research ideation and active involvement from the pharma/biotech industry. A pharma/biotech scientist was required to lead or co-lead the consortium.

  • Targeting Stress Granule Dynamics for Familial and Sporadic ALS: Joe Lewcock (Denali Therapeutics, Project Leader), Gene Yeo (University of California, San Diego), Steve Finkbeiner (Gladstone Institutes).
  • Gene Therapeutic Modulation of NMD for Treatment of ALS: Ben Shykind (Meira GTx, Co-Project Leader), Neil Shneider (Columbia University, Co-Project Leader), Gregory Petsko (Cornell University).
  • Developing human-derived antibodies to target dipeptide-repeat protein toxicity in C9ORF72 disease: Fabio Montrasio  (Neurimmune, Project Leader) Laura Ranum (University of Florida), Magdalini Polymenidou (University of Zurich), Clotilde Lagier-Tourenne (Massachusetts General Hospital).
  • Nuclear Export Inhibitor KPT-350 for C9orf72 and Sporadic ALS: Alex McCampbell (Biogen, Co-Project Leader), Jeff Rothstein (Johns Hopkins University, Co-Project Leader), Thomas Lloyd (Johns Hopkins University), Laura Ranum (University of Florida).
  • Exploiting yeast to discover small-molecule drugs for ALS caused by aberrant TDP-43, FUS, and c9orf72 dipeptide repeat protein homeostasis: Dean Brown & Nick Brandon (AstraZeneca, Co-Project Leaders), Jim Shorter (University of Pennsylvania), Steve Finkbeiner (Gladstone Institutes), Aaron Gitler (Stanford University).

Target ALS sought to encourage ideas from newly independent investigators and enrich the future of ALS research. A newly independent investigator was required to lead or co-lead the consortium.

  • Critical Assessment of the Dying Back ALS Hypothesis Using Novel iPSC and Mouse Models: Brian Wainger (Massachusetts General Hospital, Project Leader), Robert Brown Jr. (University of Massachusetts), Jean Livet (Inserm).
  • Vesicles in the Transmission of ALS: Stephanie Duguez (Ulster University, Project Leader), Susan Knoblach (Georgetown University Medical Center), Cédric Raoul (Inserm), Pierre-Francois Pradat (Pitie-Salpetriere Hospital).
  • Identification of RAN Translation Regulators as Therapeutic Targets in C9ORF72-Related ALS: Shuying Sun (Johns Hopkins University, Project Leader), Michael Bassik (Stanford University), Aaron Gitler (Stanford University), Fen-Biao Gao (University of Massachusetts), Joel Richter (University of Massachusetts).
  • The Role of NK and NKT Cells in ALS: Benjamin Murdock (University of Michigan, Project Leader), Stephen Goutman (University of Michigan).
  • Spatially resolved transcriptome wide analysis of gene expression in the spinal cord in ALS: Hemali Phatnani (New York Genome Center), Joakim Lundeberg (KTH Royal Institute), Richard Bonneau (New York University).

2013-2015
Inaugural Target Discovery and Validation Consortia

During its first three years, Target ALS funded collaborative research consortia to examine ALS disease mechanisms and candidate therapeutic targets, which is the first critical step in developing a novel therapeutic. With the aim of casting a wide net, these funding calls supported ideas from, and successfully engaged involvement of, investigators from within and outside ALS research community representing academia and pharma/biotech industry.

  • Oligodendrocyte dysfunction in ALS: Dwight Bergles (Johns Hopkins University, Project Leader), Jonah Chan (University of California, San Francisco), Tom McCown (University of North Carolina, Chapel Hill), Jeff Rothstein (Johns Hopkins University), Jude Samulski (University of North Carolina, Chapel Hill), Neil Shneider (Columbia University).
  • Unfolded protein response and endoplasmic reticulum stress in ALS: Hynek Wichterle (Columbia University, Project Leader), Hugo Bellen (Baylor College of Medicine), Kevin Eggan (Harvard University), Serge Przedborski (Columbia University), Brent Stockwell (Columbia University).
  • Motor neuron excitability and ALS: Clifford Woolf (Boston Children’s Hospital, Co-Project Leader), Solange Brown (Johns Hopkins University, Co-Project Leader), Paola Arlotta (Harvard University), Dwight Bergles (Johns Hopkins University), George Mentis (Columbia University), Neil Shneider (Columbia University), Brian Wainger (Massachusetts General Hospital), Daniel Zytnicki (University of Paris Descartes).
  • C9ORF72: Testing targets and developing models: Jeff Rothstein (Johns Hopkins University, Project Leader), Clotilde Lagier-Tourenne (University of California, San Diego), John Ravits (University of California, San Diego), Paul Taylor (St. Jude Children’s Hospital), Phil Wong (Johns Hopkins University), Kevin Eggan (Harvard University), Laura Ranum (University of Florida), Fen-Biao Gao (University of Massachusetts).
  • Unraveling mechanisms in RNA-binding protein-mediated ALS: Aaron Gitler (Stanford University, Project Leader), Michael Bassik (Stanford University), Don Cleveland (Ludwig Institute for Cancer Research), Steve Finkbeiner (Gladstone Institutes), Clotilde Lagier-Tourenne (University of California, San Diego), Jim Shorter (University of Pennsylvania), Paul Taylor (St. Jude Children’s Hospital).
  • A potassium channel and hyperexcitability screen for novel ALS therapeutics: Clifford Woolf (Boston Children’s Hospital, Project Leader), Bruce Bean (Harvard University), Kevin Eggan (Harvard University), Pharma/Biotech Partner.
  • Targeting miR-155 with antisense oligonucleotides as a therapy for ALS: Tim Miller (Washington University, Project Leader), Pharma/Biotech Partner.
  • Discovery of small molecules targeting C9ORF72 repeat RNA: Leonard Petrucelli (Mayo Clinic, Project Leader), Matthew Disney (The Scripps Research Institute), Jeff Rothstein (Johns Hopkins University), Pharma/Biotech partner.
  • Receptor-interacting protein -1 and -3 as potential targets for ALSSerge Przedborski (Columbia University, Project Leader), Pharma/Biotech partner.
  • Exploiting yeast to uncover small molecule drugs for ALS caused by aberrant TDP-43 and FUS proteostasis: Jim Shorter (University Pennsylvania, Project Leader), Aaron Gitler (Stanford University), Pharma/Biotech partner.
  • Validating ataxin 2 as a therapeutic target in ALS: Aaron Gitler (Stanford University, Project Leader), Robert Baloh (Cedars–Sinai Medical Center), Nancy Bonini (University Pennsylvania), Stefan Pulst (University of Utah), Pharma/Biotech partner.
  • Targeting the UPR for the treatment of ALS: Ray Roos (University of Chicago, Project Leader), Brian Popko (University of Chicago).
  • Preclinical foundation of urate-elevating therapy for ALS: Michael Schwarzschild (Harvard University, Project Leader), Evangelos Kiskinis (Northwestern University), Gazaleh Sadri-Vakili (Harvard University).
  • Drug efflux alterations in ALS: from mechanisms to therapy: Piera Pasinelli (Thomas Jefferson University, Project Leader), David Miller (National Institutes of Health), Davide Trotti (Thomas Jefferson University).
  • Targeting glucosyl-ceramide metabolism as a new approach to strengthen the motor units in ALS: Jean-Philippe Loeffler (INSERM, Project Leader), Frances Platt (University of Oxford).
  • Identification of therapeutic targets for cytoskeletal defects in ALS: John Landers (University of Massachusetts, Project Leader), Daryl Bosco (University of Massachusetts), Bruce Goode (Brandeis University), Steve Finkbeiner (Gladstone Institutes).
  • Enhancing proteosome function as a potential treatment for amyotrophic lateral sclerosis: Alfred Goldberg (Harvard University, Project Leader), Daniel Finley (Harvard University).
  • Astrocyte mGluR5 as a modulator of neurodegeneration in ALS: Dwight Bergles (Johns Hopkins University, Project Leader), Serge Przedborski (Columbia University), Pharma/Biotech partner.
  • Identification of small molecules that block RNA-mediated toxicity in c9ALS/FTD: Leonard Petrucelli (Mayo Clinic, Project Leader), Fen-Biao Gao (University of Massachusetts), Matthew Disney (The Scripps Research Institute).