FTD Biomarkers Initiative

Biomarkers — objective, easily measured indicators of underlying pathology — enable clinicians and researchers to accurately diagnose diseases and monitor disease progression, which are critical to clinical practice and drug development. The current lack of biomarkers for FTD contributes to diagnostic delays and errors, and hinders the assessment of drug effectiveness in clinical trials.

The FTD Biomarkers Initiative is a major new AFTD funding opportunity focused on this unmet need. Through 2018, AFTD anticipates awarding up to $5 million to support innovative approaches to the discovery and development of biomarkers that differentiate FTD from other neurodegenerative disorders, discriminate between FTD subtypes, identify underlying molecular pathologies, confirm pharmacodynamic modulation of disease pathways and track disease progression. A key feature of the initiative is the requirement for award recipients to commit to the open exchange of data and results.

2016 FTD Biomarkers Initiative Award Recipients

AFTD is pleased to announce six awards to fund cutting-edge research into the discovery of FTD biomarkers:

Principal Investigator Award Description
Randall Bateman, MD: 
Washington University St. Louis
Human CNS tau kinetics in tauopathies (2 years, $495,453). Abnormal accumulation of the protein tau occurs in Alzheimer’s disease, FTD and other neurodegenerative disorders, leading to the characterization of these diseases as tauopathies. Disease-specific alterations in the ratio of various types (isoforms) of tau are thought to be a feature that differentiates the various tauopathies. An FTD-specific pattern of tau isoforms could be the basis for a biomarker to support the evaluation of tau-based therapeutics. Dr. Bateman’s project will examine the production and clearance of tau in PSP, CBD and at-risk individuals with FTD-associated gene mutations. To do this, he will use a technique known as Stable Isotope Labeling Kinetics (SILK).
Christian Haass, PhD: 
Ludwig-Maximilians University and DZNE
sTREM2, PGRN and GRN as CSF markers for microglial activity, disease progression and therapeutic target engagement (3 years, $450,000). Mutations in two genes – GRN (progranulin) and TREM2 (triggering receptor expressed on myeloid cells 2) encode proteins that are secreted by microglia, a type of immune cell in the brain. Because inflammation is thought to play a role in the development of FTD and other neurodegenerative disorders, inflammatory proteins are promising biomarker candidates. Dr. Haass’s project will take advantage of highly specific and sensitive antibody-based assays for progranulin (PGRN, the product of the GRN gene) and soluble TREM2 (sTREM2) along with novel antibodies specific for granulins (GRNs), the small peptides derived from progranulin.
Leonard Petrucelli, PhD: 
Mayo Clinic Jacksonville
Assessing poly(GP) proteins as clinical and pharmacodynamic biomarkers of C9orf72-associated FTD (2 years, $300,000). A mutation in the C9orf72 gene has been identified as the most common cause of familial FTD and ALS. In affected individuals, the mutated gene contains a short segment of nucleotides, GGGGCC, that is repeated hundreds of times. Abnormal transcription of this recurrent G4C2 segment leads to the production of abnormal proteins; poly(GP) proteins are one example. Poly(GP) proteins are thought to play a key role in the pathogenesis of FTD and are therefore an emerging target for drug development. Dr. Petrucelli will use a new state-of-the-art technology, single molecule array (Simoa), capable of detecting a single protein molecule to detect the poly(GP) proteins in blood and CSF.
Jonathan Rohrer, MRCP, PhD: 
University College London
Identification of novel biofluid markers of tau and TDP-43 pathology (2 years, $238,686). The ability to differentiate individuals with FTD-tau pathology from those with FTD-TDP-43 pathology is essential for the development of tau- or TDP-43-specific therapeutics. However, at the present time, it is only possible to accurately determine if a given person has FTD-tau or FTD-TDP-43 if they are known to have a genetic mutation in the MAPT gene (tau) or the GRN or C9ORF72 genes (TDP-43). Dr. Rohrer’s project will identify protein isoforms and protein fragments specific to tau and TDP-43 that can be used to develop ultrasensitive assays for use in CSF and blood.
Judith Steen, PhD: 
Boston Children’s Hospital
Quantitative profiling of tau in CSF to pilot diagnoses and monitoring treatment effectiveness in FTD patients (2 years, $325,545). Dr. Steen’s laboratory has developed a promising technique specifically for identifying and measuring abnormally modified forms of tau, called the FLEXITau assay, which has been shown to accurately distinguish FTD subtypes from Alzheimer’s disease and healthy controls in post-mortem brain tissue. In this project, Dr. Steen will fine-tune the FLEXITau assay and extend testing to CSF samples with the goal of characterizing disease-specific patterns that can be used to differentiate FTD from other neurological diseases.
Judith Steen, PhD: 
Boston Children’s Hospital
Using TDP43 as a biomarker in FTD patients (2 years, $189,455). Dr. Steen’s second project will leverage the experience gained during the development of the FLEXITau assay to develop a similar FLEXI assay for TDP-43 modifications. The new FLEXITDP43 assay will be tested on brain tissue samples from FTD patients and samples from patients with other neurodegenerative disorders and optimized to establish a foundation for future evaluation in biofluids.

Biomarkers Funding Opportunities

The RFP for the next FTD Biomarkers Initiative funding cycle will be available spring 2018.

FTD Biomarkers Initiative Scientific Advisory Board

~Weninger

Stacie Weninger, PhD, Chair

Executive Director

F-Prime Biomedical Research Initiative

Kimberly Scearce-Levie, PhD

Director, Preclinical Translational Biology

Denali Therapeutics

Cha

Jang-ho Cha, MD, PhD

Global Translational Medicine

Head, Neuroscience

Novartis Institutes for Biomedical Research (NBIR)

Mackenzie

Ian Mackenzie, MD

Professor of Pathology & Laboratory Medicine

University  of British Columbia

Dunlop

John Dunlop, PhD

Vice President, Neuroscience Research

Amgen

Petrucelli

Leonard Petrucelli, PhD

Professor of Neuroscience

Mayo Clinic – Jacksonville FL

 

Forman

Mark Forman, MD, PhD

Executive Director, Translational Medicine

Merck

 

Rohrer

Jonathan Rohrer, MRCP, PhD

Clinical Lecturer & Neurologist

University College London

Principal Investigator, Genetic FTD Initiative (GENFI)

 

Grossman

Murray Grossman, MD

Professor of Neurology

Director, Penn FTD Center

University of Pennsylvania Medical School

Von Rosentiel

Philipp von Rosenstiel, MD

Senior Medical Director

Neurology, Early Clinical Development

Biogen

 

Ho

Carole Ho, MD

Chief Medical Officer

Head of Development

Denali Therapeutics

Scott Small, MD

Boris and Rose Katz Professor of Neurology

Director, Alzheimer’s Disease Research Center

Columbia University

 

Johnson

Keith Johnson, MD

Professor of Radiology & Neurology

Harvard Medical School

Director, Molecular Neuroimaging,

Massachusetts General Hospital

Zetterberg

Henrik Zetterberg, MD, PhD

Professor of Neurochemistry

University of Gothenburg

 

Knopman

David Knopman, MD

Professor of Neurology

Mayo Clinic – Rochester MN

AFTD Medical Advisory Council