Grants Portfolio

2021 Award Recipients

Holloway Postdoctoral Fellowships (2021-2023)

“Neuronal network dysfunction in neurodegenerative disease”
Daniel Okobi, MD, PhD
University of California, Los Angeles

Funding period: July 1, 2021 – June 30, 2023
Amount: $120,000 USD ($60,000/year)
Project Description: Dr. Okobi, a neurology resident and postdoctoral fellow in the laboratory of Dr. Peyman Golshani at UCLA, will use miniatured microscopes implanted in the brains of mice with an FTD-associated mutation to image brain pathways in the animals as they go about their normal activities. In addition, he will monitor the behavior of the mice, including their responses to social cues, using high-resolution video capture. Together, these state-of-the-art methods will allow Dr. Okobi to detect subtle abnormalities that represent the earliest signs of the FTD disease process.

“Dissecting the molecular consequences of C9orf72 loss in lysosomal homeostasis and ALS-FTD disease pathogenesis”
Hijai Regina Shin, PhD
University of California, Berkeley

Funding period: July 1, 2021 – June 30, 2023
Amount: $120,000 USD ($60,000/year)
Project Description: Dr. Shin, a postdoctoral fellow at the University of California, Berkeley in the laboratory of Dr. Roberto Zoncu, will build on work carried out by former AFTD postdoctoral fellow Ming-Yuan Su, PhD. Dr. Su’s research demonstrated that the protein encoded by the C9orf72 gene regulates the breakdown of damaged or obsolete proteins within a structure called the lysosome, and that the loss of functional C9orf72 in FTD disrupts this regulatory process. Dr. Shin will take this work to the next level, using cutting-edge biochemical techniques and neurons derived from patient stem cells to study the impact of the C9orf72 mutation on the lysosome in more detail. She plans to apply what she learns to devise strategies for the development of drugs that restore normal lysosome function in C9orf72-associated FTD.

“Modulating TDP-43-dependent loss of STMN2 in FTD”
Matthew Nolan, PhD
Massachusetts General Hospital

Funding period: July 1, 2021 – June 30, 2023
Amount: $120,000 USD ($60,000/year)
Project Description: Dr. Nolan will use gene editing, stem cells, and animal models to advance our understanding of the role of RNA binding proteins in FTD. Specifically, he will focus on stathmin-2, one of many proteins under the control of the RNA binding protein TDP-43. Defective TDP-43 function in FTD causes a mistake in the stathmin-2 template that reduces levels of the stathmin-2 protein. Dr. Nolan’s project seeks to identify and evaluate new drugs that target stathmin-2 as potential treatments for TDP-43-associated FTD.

2020 Award Recipients

Pilot Grants

Well-Being in FTD

“STELLA-FTD: using technology to support FTD caregivers”
Allison Lindauer, PhD
Oregon Health & Science University

Funding period: January 1, 2021 – December 31, 2021
Amount: $59,689
Project Description: While memory in people with FTD may be relatively preserved, persons diagnosed may lose insight and judgment. These changes are very hard on families – psychologically, socially, and financially. Support options offered for those with “typical” dementia, such as Alzheimer’s disease, and related dementias (ADRD), but these programs may not meet the needs of families living with FTD. Dr. Lindauer will revise an existing intervention for ADRD care partners, STELLA (Support via Technology: Living and Learning with Advancing dementia) into an intervention that meets the needs of FTD care partners. In this pilot study, family members of those with FTD will guide the revision of the existing education and support program. Using their feedback, Dr. Lindauer will tailor STELLA to meet the unique needs of care partners for those with FTD, and examine the feasibility, acceptability, and efficacy of STELLA-FTD for reducing care partner burden.

Basic Science

“Mechanisms of AMPK-mediated rescue of tauopathy in human FTD neuronal models”
Maria Catarina Silva, PhD
Massachusetts General Hospital

Funding period: January 1, 2021 – December 31, 2021
Amount: $60,000
Project Description: Tauopathy diseases like FTD are characterized by the accumulation of abnormal tau protein aggregates in the brain, leading to cell death. Yet the detrimental cellular and molecular effects of tau accumulation are not fully understood, which has contributed to ineffective development of therapeutics. Dr. Silva will focus on the characterization of the mechanism by which pharmacological activation of the enzyme AMPK improves autophagy, the process by which the body removes toxic and aggregated proteins, by measuring AMPK activity and pathway-specific biomarkers. Novel uncharacterized mechanisms of action for these drugs will also be considered. Then, the therapeutic relevance of AMPK regulation of autophagy will be determined through identification of the optimal parameters for AMPK activation that cause tau reduction and improve neuronal health in FTD. These studies will provide key mechanistic insight and preliminary data to support a translational research program aiming to advance novel therapeutic strategies for tauopathy.

AFTD-ADDF Accelerating Drug Discovery for FTD

“Development of PIKFYVE antisense oligonucleotides (ASO) treatment for FTD”
Wen-Hsuan Chang, PhD
AcuraStem Inc.

Funding period: May 3, 2021 – April 29, 2022
Amount: $165,000
Project Description: Dr. Chang will use her award to test an antisense oligonucleotide (ASO) that targets the enzyme PIKFYVE in two mouse models of FTD. Based on previous studies, she believes that blocking the enzyme will increase the clearance of damaged or misshapen proteins, such as tau and TDP-43, to prevent them from accumulating and damaging brain cells.

“Lead optimization of novel site-selective blockers of mitochondrial complex III ROS as FTD therapeutics”
Anna Orr, PhD
Cornell University

Funding period: July 1, 2021 – June 30, 2022
Amount: $135,000
Project Description: Dr. Orr and her co-investigators, Drs. Adam Orr and Subhash Sinha, will further develop a group of compounds her team developed known as S3QELs, which block harmful free radicals in brain cells that can trigger protein accumulation and inflammation. By improving the chemical and pharmacological features of these compounds, Dr. Orr and her team hope to advance a promising new approach to treating FTD.

“Preclinical efficacy study for antibody therapy in C9orf72 FTD/ALS mice”
Dieter Edbauer, MD
German Center for Neurodegenerative Diseases

Funding period: March 1, 2021 – February 28, 2023
Amount: $300,000 USD
Project Description: Dr. Edbauer and his colleagues at the German Center for Neurodegenerative Diseases will focus on on developing an immunotherapy treatment for the most common genetic mutation in people with FTD. Mutations in the C9orf72 gene lead to abnormal buildup of a protein that causes inflammation and cell death in the brains of people with FTD.

AFTD-ADDF Diagnostics Accelerator

Judith Steen, PhD
Harvard Medical School

Funding period: September 2020 – August 2022
Amount: $572,678 USD
Project Description: Dr. Steen and her team are developing a blood test to measure levels of two proteins, called tau and TDP-43, biomarkers that can signal early changes in the brains of people who will go on to develop FTD. There are no tests currently to distinguish between tau and TDP-43 pathology, a distinction which is needed to enroll FTD patients in the right clinical trials. These blood tests would provide an efficient, minimally invasive way to differentiate FTD subtypes and provide clinicians with critically needed tools to follow individual treatment response.

Rodney Pearlman, PhD
Bluefield Project to Cure FTD

Funding period: October 2019 – July 2024
Amount: $1,200,000 USD
Project Description: Dr. Pearlman of the Bluefield Project is leading this program along with Dr. Adam Boxer to evaluate blood levels of a protein called NfL (neurofilament light chain) in people who carry an inherited form of dementia called frontotemporal degeneration (FTD) who do not yet show symptoms of the disease. The success of this project will support more efficient clinical trials, which could lead to effective treatments for FTD. This study will have value beyond FTD because NfL has been identified as an important biomarker for other neurodegenerative diseases such as Alzheimer’s disease, multiple sclerosis, Parkinson’s disease and amyotropic lateral sclerosis (ALS).

Treat FTD Fund

“Dopaminergic Therapy for Frontotemporal Dementia Patients”
Giacomo Koch, PhD
Santa Lucia Foundation

Amount: $602,800
Project Description: Dr. Koch and his team at Santa Lucia Foundation will investigate whether impairment in the dopamine neurotransmitter system could be implicated in FTD. Dopamine plays a critical role in signaling reward-related information and a range of emotional processes, so any disease-related damage to the system could result in behavioral changes. Although there is clinical evidence to support the role of dopamine in FTD, the hypothesis has not been fully explored in a clinical trial. Because Rotigotene is a drug that can activate the dopamine system, it has the potential to improve executive function. Starting from this knowledge, this project aims to test the safety and efficacy of Rotigotine, a dopaminergic agonist, in bv-FTD patients. Additionally, Dr. Koch’s team will perform neurophysiological and neuroimaging investigations that will allow them to explore the neural correlates underlying the effects induced by their proposed intervention. The proposed project could deepen our understanding of the pathophysiology of neurotransmitter dysfunction involved in FTD and hopefully provide a valid treatment for cognitive dysfunction in FTD patients. This research is a multi-site, randomized double-blind, placebo-controlled clinical trial that will test 75 patients over 24 weeks of treatment with Rotigotene or placebo. Successful completion of the trial will determine whether Rotigotene treatment can successfully improve behavior and biomarkers of neurodegeneration in FTD patients.

“Non-Invasive Brain Stimulation for Gamma Induction and Cognitive Enhancement in FTD”
Emiliano Santarnecchi, PhD
Harvard Medical School

Amount: $1,959,841
Project Description: In FTD, the balance between cortical excitation and inhibition becomes abnormal. Research has shown that a non-invasive brain stimulation approach called transcranial Alternating Current Stimulation (tACS) can modulate rhythmic brain activity by means of low amplitude alternating currents applied to the head. This approach has the potential to rebalance brain oscillation patterns and even enhance cognition. The proposed research is a multi-site, randomized double-blind, placebo-controlled clinical trial that will test 50 patients over 6 weeks of treatment with tACS or sham stimulation (placebo). Successful completion of the trial will determine whether tACS treatment can improve behavior and brain activity in FTD patients.

2019 Award Recipients

Pilot Grants

Nonpharmacological Therapies and Tools

“Improving the ability of family caregivers to care for persons living with frontotemporal dementia through an innovative simulation program”
Linda Wilson, PhD
Drexel University
Funding period: July 1, 2019 – June 30, 2020
Amount: $60,000
Project Description: Coping with FTD symptoms can be difficult and distressing for caregivers, who often know little about the disease or effective ways to address challenging behaviors. Dr. Wilson’s project will seek to give family caregivers the knowledge and skills needed to deal confidently with FTD symptoms through the use of simulated care scenarios that replicate challenging situations they encounter in daily life. Dr. Wilson will follow up with participants to determine how well the skills learned in the simulation laboratory transfer to the home setting and hopes to ultimately develop a standardized simulation program that can be used by community-based organizations serving families with FTD.

Basic Science

“Investigating the role of lysosomal progranulin in FTD”
Andrew Arrant, PhD
University of Alabama at Birmingham
Funding period: January 1, 2020 – December 31, 2020
Amount: $60,000
Project Description: Mutations in the progranulin (GRN) gene, one of the most common causes of genetic FTD, lead to a reduction in the progranulin protein it encodes and a corresponding loss of progranulin’s protective and anti-inflammatory actions. However, it is unclear whether the beneficial effect of progranulin is due to its interaction with progranulin receptors on the surface of cells or to its activity inside cells, where it regulates the function of lysosomes. Dr. Arrant will attempt to answer this question using a novel form of human progranulin that only acts on lysosomes to determine if this restricted form of the protein can rescue neurons derived from mice with a progranulin mutation. In addition, he will develop mice genetically engineered to express lysosome-specific progranulin to further study the interaction between lysosome function and neurodegeneration.

Susan Marcus Translational Research

“Optimization of bifunctional anti-tau intracellular antibody delivery into human neurons”
David Butler, PhD
Regenerative Research Foundation

Funding period: January 1, 2020 – December 31, 2020
Amount: $60,000
Project Description: The defining pathological feature of FTD-tau, one of a group of neurodegenerative disorders known collectively as tauopathies, is the abnormal accumulation of tau in neurons. The goal of Dr. Butler’s project is to develop genetically engineered intrabodies – antibodies designed to bind to targets inside cells rather than on the cell surface – that recognize tau and also contain a molecular tag that diverts the bound tau to the cell’s normal degradation pathway. As a result, toxic tau is broken down rather than accumulating. Dr. Butler will determine the safety and efficacy of these tau-lowering intrabodies in 3-dimensional human organoids, or “mini-brains,” derived from patient-specific induced pluripotent stem cells, the first step in developing intrabody-based therapeutics.

FTD Biomarkers Initiative

“Accelerating tau PET imaging through head to head comparison of novel radiotracers”
Tammaryn Lashley, MD, PhD and Kerstin Sander MD
University College London

Funding period: December 14, 2018 – December 13, 2020
Amount: $247,272

“Cryo-electron microscopy of brain-derived TDP-43 filaments to rationally design PET ligands for FTD”
Anthony Fitzpatrick, PhD
Columbia University Medical Center

Funding period: November 1, 2018 – October 31, 2019
Amount: $150,000

“Assessing poly(GP) proteins as clinical and pharmacodynamic biomarkers of C9ORF72-associated FTD”
Leonard Petrucelli, PhD
Mayo Clinic Jacksonville

Funding Period: October 1, 2019 – September 30, 2021
Amount: $565,248

“Targeting structural alterations of TDP-43 and other proteins to develop biomarkers for FTLD subtypes”
Magdalini Polymenidou, PhD
University of Zurich, Switzerland

Funding Period: September 1, 2019 – August 31, 2022
Amount: $532,122

AFTD Postdoctoral Fellowships (2019-2021)*

Basic Science

“A structural approach to rescuing C9orf72 haploinsufficiency in ALS/FTD”
Ming-Yuan Su, PhD
The Regents of the University of California

Funding period: July 1, 2019 – June 30, 2021
Amount: $110,000 USD ($55,000/year)
Project Description: The C9orf72 protein encoded by the C9ORF72 gene mutated in hereditary FTD and ALS exists as part of a large stable complex with two other proteins, SMCR8 and WDR41.  In her postdoctoral project, Dr. Su will utilize cryo-electron microscopy to determine the structure of this C9orf72SMCR8WDR41 complex and another technique, HDX-coupled mass spectrometry, to learn more about how the three proteins interact.  She will then attempt to identify small molecule compounds that can stabilize the complex, slowing its breakdown, and determine if stabilization can compensate for the reduction in C9orf72 due to the mutation in FTD and improve the survival of neurons created from patient-derived stem cells. If so, these compounds could be the starting point for the development of effective treatments for FTD associated with the C9orf72 mutation.

Clinical Research

“Identification of an RNA-based biomarker for FTD”
Oriol Dols Icardo, PhD
Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau

Funding period: January 1, 2020 – December 31, 2021
Amount: $110,000 USD ($55,000/year)
Project Description: The abnormal accumulation of tau, TDP-43, and other proteins that is the defining pathological feature of FTD may be preceded by alterations in RNA expression. Such changes in RNA could be a potential biomarker for early-stage FTD. In his postdoctoral project, Dr. Icardo will characterize the transcriptome of the frontal cortex in FTD-tau, FTD-TDP-43, and FTD-FUS compared to healthy controls. He will also compare TDP-43 associated RNA alterations in FTD with RNA alterations in the motor cortex of people with ALS. FTD-specific changes identified in brain will be further evaluated in RNA from exosomes of patients representing FTD clinical subtypes. Differences in CSF RNA that reliably and consistently differentiate FTD subtypes or individuals with FTD from those who do not could be the basis of a fluid biomarker as well as promising targets for RNA-based FTD treatments.

*First year independent fellowships awarded in basic and clinical research