Funded Projects

Target ALS has awarded five Springboard Fellowships to emerging scientists. The program was established to support senior lab fellows as they transition to independent academic tenure track or equivalent positions and to support their continued focused on ALS research.

• Does the disruption of lipid droplets by glial Tau and TDP-43 drive ALS/FTD?
  Lindsay Goodman, Baylor College of Medicine
• Mapping mRNA microenvironments to reveal mechanisms of TDP-43 toxicity rescue
  Lindsay Becker, Princeton University
• Defining the multi-faceted role of TDP-43 in RNA metabolism in amyotrophic lateral sclerosis
  Yi Zeng, Stanford University
• Uncovering Mechanisms of the Immunovascular Axis in Resilience Against ALS Pathologies
  Chloe Lopez-Lee, Icahn School of Mount Sinai
• Identification of New Targets to Modulate TBK1 Kinase Activity in ALS
  Julie Smeyers, University of California San Francisco

Target ALS has awarded grants to four new Drug Discovery Consortia that unite academic scientists and industry partners to pursue innovative mechanisms of disease, generate translational data, and accelerate the development of next-generation treatments. This program is designed to bring new, biologically rational therapeutic targets into the ALS clinical pipeline.

• Optimizing Antisense Oligonucleotides to Safely Knock Down CCDC146
  Johnathan Cooper-Knock (University of Sheffield), Xibo Li (SynOligo), Sai Zhang (Yale University), Justin Ichida (University of Southern California), Ana Jovičić (Genentech)
• Advancing SYF2 Antisense Oligonucleotides to Restore TDP-43 Function
  Wen-Hsuan Chang (AcuraStem), Philip Wong (Johns Hopkins University), Wilfried Rossoll (Mayo Clinic Jacksonville), Marcel van der Brug (AcuraStem)
• Developing a Small Molecule to Correct UNC13A Splicing Defects in Sporadic ALS
  Christopher Rusconi (Ladder Therapeutics d.b.a. Serna Bio), Sami Barmada (University of Michigan), Jason Swedlow (University of Dundee), Alistair Langlands (University of Dundee), Ashkan Javaherian (Ladder Therapeutics d.b.a. Serna Bio), Rabia Khan (Ladder Therapeutics d.b.a. Serna Bio)
• Enhancing Motor Neuron Resistance to TDP-43–Driven Splicing Defects
  Esteban Mazzoni (NYU Langone Health System), Molly Gale-Hammell (NYU Langone Health System)

Target ALS has awarded funding to a project led by two prominent ALS researchers to detect cryptic peptides associated with TDP-43 pathology, seen in ~97% of ALS cases, for biomarker development. This work could produce a reliable, non-invasive way to monitor disease progression and response to treatment in people living with ALS.

• Generation of antibodies to HDGFL2 and IgLON5 cryptic peptides and development of highly sensitive immunoassays for biomarker analysis in patients with ALS/FTD
  Dr. Leonard Petrucelli, Ph.D., Mayo Clinic, Jacksonville, and Dr. Nicholas Ashton, Banner Sun Health Research Institute

Three research projects have been selected for in-kind grants through the In Vivo Target Validation Program, an initiative that supports proof-of-concept studies for cutting-edge ALS therapies in living models of disease. These grants, conducted in partnership with contract research organization Biospective, help scientists test whether their experimental therapies can engage targets and modify disease progression in ALS-relevant mouse models.

• LINE-1 Inhibitors: Halting Neuroinflammation at the Source
  Dr. Sarah Knutson, ROME Therapeutics
• Targeting GPR17: A New Path to Protect Nerve Support Cells
  Dr. Marta Fumagalli, Università degli Studi di Milano
• Gene Therapy to Protect Motor Synapses
  Dr. Brian McCabe, EPFL Switzerland

Three research consortia have been awarded Target ALS funding to develop next-generation gene therapies for ALS. This competitive initiative was designed to accelerate cutting-edge research aimed at developing novel DNA- and RNA-targeting therapies for both sporadic and familial ALS. The selected teams represent powerful collaborations, including between academia and industry, uniting complementary expertise to advance technologies with the potential to transform ALS treatment.

• Nonviral transferrin-mediated Cas9 delivery to the CNS enabling CRISPR gene therapy for C9orf72-ALS
  Claire Clelland (UCSF, leader), Neel Singhal (UCSF) and Chris Koth (Denali Tx)
• Advancing RNA-targeting CRISPR modalities for treatment of FUS-linked ALS
  Thomas Gaj (U Illinois, leader) and Neil Shneider (Columbia U)
• Developing a Dual Targeting siRNASO Oligonucleotide Therapy for Amyotrophic Lateral Sclerosis Patients
  Evangelos Kiskinis (Northwestern U, leader), Jonathan Watts (UMass Chan)

Collaborative groups pioneering the discovery and development of novel disease progression and patient stratification biomarkers will have their efforts bolstered as Target ALS awards five outstanding projects with the Biomarker Consortia Grant. Biomarkers are needed to stratify patient populations, understand responses to therapeutics, and quantify disease progression.

• Translating Novel ALS and FTD Fluid Biomarkers of TDP-43 Pathology Towards the Clinic
  Dr. Arti Patel (Novartis), Professor Anja Schneider (DZNE), Dr. Alex Thompson (University of Oxford), Dr. Pegah Masrori (KU Leuven)
• Liquid Biopsy for Amyotrophic Lateral Sclerosis Using Epigenetic Signatures from Plasma Cell-Free DNA
  Professor Albert La Spada (University of California Irvine), Dr. Sebastian Michels (Ulm University), Dr. Wolfgang Ruf (Ulm University), Professor Wei Li (UCI), Dr. Arthur Cheung (TWIST Biosciences)
• Understanding the Relevance of TDP-43-Induced Cryptic Exon Expression for Synaptic Dysfunction in ALS
  Professor Philip Van Damme (KU Leuven), Professor Rosa Rademakers (VIB), Dr. Eugeen Vanmechelen (Adx NeuroSciences), Professor Koen Poesen (KU Leuven), Professor Dietmar Thal
• KCNQ2 Biomarker for Precision Medicine in ALS
  Dr. Yossi Dagon (QurAlis), Professor Evangelos Kiskinis (Northwestern University), Professor Nicholas Seyfried (Emory University), Dr. Johan Skog (Exosome Diagnostics)
• Transposable Element in Neuron Derived Extracellular Vesicles: Patient Selection and Treatment Response Biomarker
  Dr. Erez Eitan, Ph.D. (NeuroDex, Inc.), Dr. Marta Garcia Montojo (Twilight Neuro), Dr. Alain Prochiantz (BrainEver Pharma), Dr. Avindra Nath (NINDS)

With a goal to accelerate the development of novel therapeutics, two researchers have been awarded an in-kind grant, supporting the evaluation of the effect of modulating a candidate therapeutic target on the ALS phenotypes in the standardized AAV9 G4C2 (149) C9orf72 mouse model. This initiative is in collaboration with the ALS Association and experiments will be conducted at The Jackson Laboratory.

• Assessing the Efficacy of Niclosamide in the C9orf72 mouse model of ALS
  Dr Savina Apolloni, Tor Vergata University of Rome
• Autophagy modulation as a potential therapeutic approach for C9orf72 ALS
  Dr John Blackwood, Samsara Therapeutics Ltd

Target ALS awarded six Basic Biology Consortia focused on understanding the fundamental biology of sporadic ALS, which comprises 90% of ALS cases. These exciting research projects aim to drive identification of novel drug targets and biomarkers, accelerating the development of treatments for all people who live with this disease.

• A Nucleolin/Importin Axonal Axis in ALS
  Eran Perlson (Tel-Aviv University), Amir Dori (Sheba Medical Center, Tel-Hashomer), Mike Fainzilber (Weizmann Institute of Science), Zevik Melamed (Hebrew University of Jerusalem)
• Deep FUS: Stratifying sALS Along the FUS Axis Using Multimodal Profiling
  Steven Altschuler (University of California, San Francisco), Stormy Chamberlain (F. Hoffmann-La Roche Ltd), Cathy Lomen-Hoerth (University of California, San Francisco), Sally Temple (Neural Stem Cell Institute), Lani Wu (University of California, San Francisco)
• Investigating Glial-Immune Crosstalk in Modulating Sporadic ALS Survival
  Jack Humphrey (Icahn School of Medicine at Mount Sinai), Philip Hasel (University of Edinburgh), Andrea Malaspina and Rickie Patani (The Francis Crick Institute, UCL)
• Mechanisms of Glial-Associated TDP-43 Pathology and Contributions to Neurodegeneration
  Rita Sattler (Barrow Neurological Institute), Yuna Ayala (St. Louis University), Christopher Donnelly (University of Pittsburgh), Patrick Pirrotte (Translational Genomics Research Institute), Kendall Van Keuren-Jensen (National Institute on Aging)
• SISMIC-TDP-43: Structure-Based Identification of Small Molecules Interacting with and Counteracting TDP-43 Aggregation
  Morwena Latouche (Paris Brain Institute), Emanuele Buratti (International Centre for Genetic Engineering & Biotechnology), Jean-Christophe Cintrat (Commissariat à l’énergie Atomique et aux Énergies Alternatives), Olivier Sperandio (Institut Pasteur).
• Neuronal Innate Immune Pathways That Drive Cell Death and Inflammation in ALS
  Mark Albers, Clotilde Lagier-Tourenne, Brian Wainger (Massachusetts General Hospital), Isaac Chiu (Harvard University)

Our Neurology Resident Grants Program supports innovative research projects from early-stage clinician scientists that aim to advance therapeutic and biomarker development for ALS. Three projects from outstanding neurology residents have been selected for funding.

• Multimodal Machine Learning: Disentangling Disease Heterogeneity and Enhancing Clinical Understanding
  Robert McFarlane, Trinity College Dublin
• TDP-43 Seed Amplification Assays for Diagnosing ALS
  Sarah Smith, Brigham & Women’s Hospital, Harvard Medical School
• Longitudinal Whole-Body Muscle MRI as a Biomarker for Disease Progression and Therapeutic Development in ALS
  Oliver Ziff, University College London

Target ALS has awarded five In Vivo Target Validation grants aimed at advancing proof-of-concept studies for potential therapeutics in a TDP-43 mouse model of ALS. In collaboration with Biospective, this initiative seeks to accelerate the transition from preclinical research to clinical trials.

• Evaluation of a Novel CK1d Inhibitor in the TDP-43 ΔNLS Mouse Model for ALS
  Nick J Brandon at Neumora Therapeutics
• A Brain-Penetrant Small Molecule Modulator of TDP-43 Condensates Reduces Cytoplasmic TDP-43 Pathology In Vitro and In Vivo
  Jesse Lai at Dewpoint Therapeutics
• Human-Derived TDP-43 Intrabodies to Restore TDP-43 Function in ALS
  Nikole Zuniga Quiroz at Mabylon AG
• Investigation of a Mitochondrial Pore Inhibitor in the Low-Dox DeltaNLS Mouse Model
  Ovadia Lazari at NRG Therapeutics Ltd
• Boosting Lysosomal Function for Benefit in ALS
  Baris Bingol at Genentech

Target ALS is committed to supporting clinicians working with ALS patients to conduct important translational research that will better our understanding of the disease. We funded five ALS clinicians early in their careers to further their scientific research.

• Phenotype-driven drug target discovery for ALS/FTD using brain single nuclear transcriptomics and the organ chip models pairing iPSC organoids and peripheral blood immune cells
  Mai Yamakawa, University of California, Los Angeles
• Theragnostic potential of profiling CD8+ T-cells in peripheral tissues of people with pre-symptomatic sporadic ALS
  Jenna Gregory, University of Aberdeen
• Identifying Upper Motor Neuron Pathology and Molecular Signatures in the ALS Motor Cortex
  Frank Diaz, Cedars-Sinai Medical Center
• Mapping the microglial heterogeneity and its use as biomarker in C9orf72-ALS and sporadic ALS
  Pegah Masrori, University Hospitals Leuven
• Revealing neuroprotective and neurotoxic T cell responses in amyotrophic lateral sclerosis
  Caroline Ingre, Karolinska Institutet

As part of our commitment to drug discovery, Target ALS and The ALS Association are funding six exciting proof-of-concept studies to be performed at The Jackson Laboratory. Candidate therapeutics for C9orf72 ALS (the most common genetic cause of ALS) will be tested in the standardized AAV9-based 149 G4C2 repeat C9orf72 mouse model (Chew et al., 2019).

• Adrian Isaacs
  University College London
• Jesse Lai
  Dewpoint Therapeutics
• Wenting Guo
  French National Institute of Health and Medical Research (INSERM)
• Nick J. Brandon
  Neumora Therapeutics
• Andrew Pincetic
  Alector
• Maj-Linda Selenica
  University of Kentucky

Target ALS New Academic Investigator Grants support scientists who have established their own lab in the last five years through a 3-year grant, access to Target ALS core facilities during the grant period, and an opportunity to join us at our annual meeting. This year, we awarded six New Academic Investigator grants to promising young researchers, supporting the advancement of their ideas as the next generation of leaders in ALS research.

• Creation of the Precision Genome Therapy Toolkit to facilitate CRISPR gene editing for ALS
  Claire Clelland, University of California, San Francisco
• Modified TDP-43 as a template for diagnosis and imaging tools for ALS/FTD
  Javier Oroz, Consejo Superior de Investigaciones Científicas
• Unraveling the role of C9orf72 in organelle identity and interactions in neurons
  Ginny G. Farias, Utrecht University
• Defining how Tankyrase functions with TDP-43 in ALS/FTD disease progression
  Leeanne McGurk, University of Dundee
• Elucidating the nature and role of immunoreactivity in the pathophysiology of ALS
  David Gate, Northwestern University
• Probiotic therapies for ALS/FTD
  Aaron Burberry, Case Western Reserve University

Target ALS Springboard Fellowships facilitate the transition from postdoctoral fellowship to independent faculty appointment or the industry equivalent through a portable 3-year grant and access to Target ALS Core facilities. This year, we awarded seven Springboard Fellowships to emerging scientists, supporting their continued interest in ALS and paving the way for future breakthroughs.

• Investigating Ataxin-3 as a novel modifier of TDP-43 pathology in ALS
  Frederick Arnold, University of California, Irvine
• Decoding non-cell autonomous processes in motor neuron selective vulnerability in ALS
  Aude Chiot, Oregon Health and Science University
• RNA-directed therapy for C9ORF72-linked ALS using zinc finger nucleases
  Kathryn Morelli, University of Vermont
• The role of TDP-43 in regulating the m6A-epitranscriptome of human neurons – potential implications for selective vulnerability mechanisms during ALS
  Jose Norberto “Jobert” Sagullo Vargas, University College London
• Exploring the regulation mechanism and epigenetic function of LINE1 RNA in ALS/FTD
  Yini Li, Johns Hopkins University School of Medicine
• The development of therapeutic strategies for ALS by targeting DAXX
  Yang Liu, Johns Hopkins University School of Medicine
• Impact of UBQLN2P506T on autophagy, bioenergetics, and inflammation in iPSC-derived cortical neurons, lower motor neurons and microglia
  Juliet Goldsmith, University of Pennsylvania

The members of the consortia receiving funding are as follows:

• Correcting Aberrant Splicing of UNC13A as a Therapeutic Approach for ALS and FTD:
  Ryan Morrie and Shila Mekhoubad (Maze Therapeutics, Project Co-Leaders), Noa Lipstein (Leibniz-Forschungsinstitut für Molekulare Pharmakologie), Sami Barmada and Michael Bekier (Univeristy of Michigan), and Aaron Gitler (Stanford University).
• RNA granules as novel therapeutic targets in ALS/FTD:
  Joe Lewcock (Denali Therapeutics, Project Leader), Eugene Yeo, John Ravits, and Eric Bennett (University of California, San Diego).
• Targeting selective autophagy mechanisms in ALS:
  Lesley Kane (Denali Therapeutics, Project Leader), Daniel Mordes and Jayanta Debnath (University of California, San Francisco).
• Development of Small Molecule Drugs that Alleviate TDP43 Mislocalization to Treat ALS:
  Suganya Selvarajah (Prosetta Biosciences, Project Leader), Steven Finkbeiner (Galdstone Institute), and Yongjie Zhang (Mayo Clinic Jacksonville).
• Leveraging the new therapeutic modality of divalent siRNA to investigate and treat C9orf72-driven ALS:
  Stephen McDonough (Atalanta Therapeutics, Project Leader) Jeffrey Rothstein and Alyssa Coyne (Johns Hopkins University), and Cathleen Lutz (Jackson Labs).
• Therapeutic targeting of Antisense C4G2 repeat RNA in C9orf72 ALS/FTD:
  Paymaan Jafar-nejad (Ionis Pharmaceuticals), Sophie Parmentier-Batteur (Biogen), and Jeffrey Rothstein and Alyssa Coyne (Johns Hopkins University).

Expanding the pipeline of therapeutic targets rooted in a strong biological rationale is key to maximizing the chance of success in future clinical trials. In October, the Target ALS Independent Review Committee (IRC) identified seven new collaborative projects for funding.

The members of the selected consortia receiving funding are as follows:

• Probing RNA-binding protein aggregates at the nanoscale using in-silico-designed aptamers.
  Mathew Horrocks (University of Edinburgh, Project Leader), Jenna Gregory (University of Aberdeen), Gian Tartaglia and Elsa Zacco (Italian Institute of Technology), and Neil Shneider (Columbia University).
• Exploring the landscape of ALS genetics with machine learning and optical pooled screens.
  Jonathan Cooper-Knock (University of Sheffield, Project Leader), Michael Snyder (Stanford University), Ophir Shalem (University of Pennsylvania), and Eran Hornstein (Weizmann Institute of Science).
• Scalable phenotyping of ALS-associated point mutations, using base editor pooled genomic screens and a single cell transcriptomic readout.
  Eran Hornstein (Weizmann Institute of Science, Project Leader), Hemali Phatnani (New York Genome Center), Pietro Fratta (University College, London), and Michael Ward (NIH/NINDS).
• Investigation of Ms4a genes as potential novel therapeutic targets for ALS.
  Paul Greer (Project Leader), Robert Brown, and Dorothy Schafer (UMass Chan Medical School).
• Evaluation of Novel Strategies to Ameliorate Aberrant Central Motor Synapse Elimination in ALS.
  Brian McCabe and Bernard Schneider (Swiss Federal Institute of Technology, Project Co-Leaders), and Sabine Liebscher (Ludwig-Maximilians University).
• Does the accumulation of disease-associated forms of TDP-43 in platelets parallel ALS pathophysiology in the nervous system?
  Ruth Luthi-Carter (AC Immune SA, Project Co-Leader), Robert Bowser (Barrow Neurological Institute, Project Co-Leader), Abdulbaki Agbas (Kansas City University), and Emanuele Buratti (International Centre for Genetic Engineering and Biotechnology).
• Targeting hypermetabolism for ALS treatment.
  Francesco Roselli and Johannes Dorst (Ulm University, Project Co-Leaders), Luc Dupuis (Université de Strasbourg), and Liang Li (University of Alberta).

The consortium members receiving funding for this project are as follows:

• Digital measurement of gait as a potential biomarker for ALS-FTSD.
  Angela Genge (McGill University, Project Leader), Dr. Nicolas Dupre (CHU de Quebec-Universite Laval), Sanjay Kalra (University of Alberta), and Kasturi Telepatra (Regeneron Pharmaceuticals)

In August, Target ALS, Gates Ventures, and the Alzheimer’s Drug Discovery Foundation (ADDF) announced the first four award recipients in a new initiative to identify and develop biomarkers for Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD) or Frontotemporal Dementia (FTD).

Three projects were selected. The members of the consortia receiving funding are as follows:

• A low-burden, high-frequency prognostic digital speech biomarker to improve future confirmatory ALS and FTD trials.
  Johannes Tröger (ki:elements, Project Leader), Jessica Robin (Winterlight Labs), and Anja Schneider and Andreas Hermann (German Center for Neurodegenerative Diseases).
• Novel biomarkers to detect and monitor TDP-43 pathology in ALS/FTD.
  Pietro Fratta (University College, London, Project Leader), Michael Ward (NIH/NINDS), and Leonard Petrucelli and Mercedes Prudencio (Mayo Clinic).
• Ultrasensitive detection of TDP-43 pathology with RT-QuIC of nasal swabs.
  Magdalini Polymenidou (University of Zurich, Project Leader), Gianluigi Zanusso (University of Verona), and Giuseppe Legname (Trieste International School for Advanced Studies).

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.

• Development and validation of novel biofluid biomarker immunoassays employing SupraAntigen(TM)-induced antibodies to detect TDP-43-associated neuropathologies in ALS:
  Ruth Luthi-Carter (AC Immune, Project Leader), Ghazaleh Sadri-Vakili, Clotilde Lagier-Tourenne, Steven Arnold and James Berry (Massachusetts General Hospital)
• Identify disease-associated fluid biomarkers reflecting loss of TDP-43 activity and dysregulation of TGFβ signaling in the brain:
  Yi Chen (Biogen, Project Leader), Jiou Wang and Phil Wong (Johns Hopkins University)
• Neuron-derived exosomes as a biomarker platform for Amyotrophic lateral sclerosis:
  Erez Eitan (NeuroDex Inc., Project Leader), 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, Project Leader), Tim Miller and Cindy Ly (Washington University), Randall Bateman (Washington University)

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.

• HDAC6 as a therapeutic target and biomarker for ALS and FTD:
  Janice Kranz (Eikonizo Therapeutics, Project Leader), 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., Project Leader), 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, Project Leader), 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., Project Co-Leaders), 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, Project Leader), 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, Project Leader), Fen-Biao Gao (University of Massachusetts Medical School), Sami Barmada (University of Michigan Medical School)

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).

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.

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.

• Uncovering novel genetic modifiers of mutant C9ORF72-related toxicity:
  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).

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 Transport Modifier 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).

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 the 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).
• The Role of Motor Neuron Excitability in ALS Pathogenesis & Potassium channel openers for the treatment of 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: Roles for TDP-43, FUS, and beyond:
  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).
• Ion channel screen for development of novel treatments for ALS:
  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.
• Targeting C9ORF72 loss of function in c9ALS/FTD: Identification of small molecules/siRNAs that target epigenetic modifiers and increase wild-type C9ORF72:
  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 ALS:
  Serge 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:
  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).