Research Grants 2023

RESEARCH GRANTS

It is very important to our family to make a strong commitment to the Hereditary Disease Foundation. It is foremost in our hearts that there will someday be a cure or a way to improve the lives of those who are at risk of Huntington’s disease. We have great confidence in the work that the Foundation is doing and we understand the necessity to support these dedicated and brilliant scientists who are working towards this goal.

Lauren Baker Pinkus Member, Board of Directors Hereditary Disease Foundation

The Hereditary Disease Foundation provides funding for research that advances the discovery and development of treatments for Huntington’s disease (HD) and other brain disorders. We are passionate about finding and funding the most promising, creative and paradigm-changing research. Data generated with HDF grants has allowed many researchers to receive major long-term funding from other sources, including the National Institutes of Health.

Natalia Barbosa, PhD

Stanford University, Palo Alto, CA

Costanza Ferrari Bardile, PhD

University of British Columbia, Vancouver, Canada

Marta Biagioli, PhD

University of Trento, Italy

Mariacristina Capizzi, PhD

Paris Brain Institute, France

Marissa N. Dean, MD

University of Alabama at Birmingham

Amit Laxmikant Deshmukh, PhD

The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada

Hassan Fakih, PhD

University of Massachusetts Chan Medical School

Terence Gall-Duncan, PhD

The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada

Michelle Gray, PhD

University of Alabama at Birmingham

Carolina Gubert, PhD

The Florey Institute of Neuroscience and Mental Health

University of Melbourne, Australia

Hyeseung Lee, PhD

Picower Institute for Learning and Memory

Massachusetts Institute of Technology, Cambridge

Ryan Lim, PhD

University of California, Irvine

James Mackay, PhD

University of British Columbia, Vancouver, Canada

Srivathsa Magadi, PhD

Linköping University, Sweden

Zachariah L. McLean, PhD

Massachusetts General Hospital

Harvard University, Boston

A. Jenny Morton, PhD

University of Cambridge, England

Christopher Ng, PhD

Massachusetts Institute of Technology, Cambridge

Izabella Pena, PhD

Picower Institute for Learning and Memory

Massachusetts Institute of Technology, Cambridge

Ashutosh Phadte, PhD

Thomas Jefferson University, Philadelphia, PA

Steven Pogwizd, MD

University of Alabama at Birmingham

Piere Rodriguez-Aliaga, PhD

Stanford University, Palo Alto, CA

Jennie C. Lacour Roy, MD, PhD

Massachusetts General Hospital

Harvard Medical School, Boston

Sophie St-Cyr, PhD

Children’s Hospital of Philadelphia

University of Pennsylvania

Partha S. Sarkar, PhD

University of Texas Medical Branch at Galveston

Chiara Scaramuzzino, PhD

Grenoble Institut des Neurosciences, France

Sridhar Selvaraj, PhD

Stanford University, Palo Alto, CA

Joan Steffan, PhD

University of California, Irvine

Andrew F. Teich, MD, PhD

New York Brain Bank

Columbia University Irving Medical Center, NY

Ray Truant, PhD

McMaster University, Hamilton, Ontario, Canada

Andrew S. Yoo, PhD

Washington University School of Medicine, St. Louis, MO

NATAliA BARBoSA, PHD

Mentor: Judith Frydman, PhD

Institution: Stanford University, Palo Alto, CA

Project Title: Linking proteostasis and mitochondrial dysfunction in Huntington’s disease

2022 Nancy S. Wexler Young Investigator Prize Recipient

Aprominent feature of Huntington’s disease is the formation within neurons (brain cells) of large protein clumps which participate in neuronal break down. However, it remains unclear just how these protein clumps impair essential cellular components, for example, mitochondria, which are essential for energy metabolism and signaling processes within neurons. Nor do we know how the clumps might interfere with proteostasis, the process that oversees protein synthesis, folding, and degradation within cells. We do know that disrupting proteostasis could lead to the breakdown of multiple cellular processes. Dr. Barbosa investigates, on a molecular level, the connections between mitochondrial collapse and proteostasis in HD across biochemical, genetic, and structural fronts. Understanding these connections may change the way we think about Huntington’s disease, potentially opening up new strategies for effective therapeutic interventions.

CoSTANzA FERRARi BARDilE, PHD

Mentor: Mahmoud Pouladi, PhD

Institution: University of British Columbia, Vancouver, Canada

Project Title: Understanding the role of oligodendroglia, brain cells that support neurons, in the pathology of Huntington’s disease

Oligodendrocytes, a type of brain cell responsible for aiding communication between different brain regions and providing support to neurons, may be affected by the Huntingtin mutation. Some evidence from mouse models suggests that pathology in oligodendrocytes may contribute to the disease. This project aims to investigate the ways in which the HD mutation affects human oligodendrocytes, potentially pointing to ways of delaying the disease or lessening its severity.

The Nancy S. Wexler Young Investigator Prize is awarded annually to an HD researcher whose work reflects the highest caliber of excellence, diligence and creative thinking. Past recipients pictured (l to r): Sarah Hernandez (2021), Natalia Barbosa (2022), Osama Al-Dalahmah (2020).

Matt Teuten/HDF

MARTA BiAGioli, PHD

Institution: University of Trento, Italy

Project Title: A circular RNA molecule to modify Huntington’s disease phenotypes

No successful disease modifying treatments are currently available for Huntington’s disease. However, researchers worldwide are pursuing strategies to lower levels of the mutant huntingtin protein and seeking methods to influence the rate of progression of the disease. To that end, Dr. Biagioli’s project investigates the function of circHTT , a novel circular RNA molecule which her laboratory group recently discovered. This circular RNA is produced from the same genetic region that is altered in HD. CircHTT is a very stable RNA molecule and its levels are high in the brain and are strongly increased in the presence of the HD mutation. Dr. Biagioli’s project seeks to determine how circHTT functions in the cells and in the brain. She will investigate if increasing or decreasing circHTT levels may influence huntingtin protein abundance and deleterious processes in HD. A larger goal is to study the potential of circHTT as new tool to control huntingtin expression and ultimately to modify destructive cellular features associated with the disease.

MARiACRiSTiNA CAPizzi, PHD

Institution: Paris Brain Institute, France

Project Title: Repairing the communication between brain cells in HD

Our brain is a community of cells – including neurons – organized into a complex network that shares information crucial for our body to function. The information is collected in a “hub” (called the Axonal Initial Segment) located at the entrance of the axon – a cable-like structure extending out from the body of the neuron. Here information is loaded like cargo onto “railways” called microtubules to travel over long distances to its target destination. Normally only cargos of a specific size capable of traveling at sufficient speed are allowed onto these railways. Dr. Capizzi hypothesizes that, in Huntington’s disease, the rails and the hub become damaged so that the cargos are loaded but travel too slowly. The information gets mixed up and does not properly reach its target. Dr. Capizzi will unravel how the hub organization and function are altered in Huntington’s disease.

©UniTrento ph. Federico Nardelli

AMiT lAxMikANT DESHMukH, PHD

Mentor: Christopher E. Pearson, PhD

Institution: The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada

Project Title: Role of FAN1 and MLH proteins as modifiers of the CAG repeat mutation in Huntington’s disease

Ongoing CAG expansions in the brains of people born with the expanded huntingtin gene are thought to drive disease age of onset and the rate of symptom progression, such that arresting or reversing these continuing expansions may be a therapeutic avenue. Two DNA repair proteins, FAN1 and MLH1, appear to play an important role in determining age of onset and disease progression. Both modifiers influence continuing CAG expansions, with FAN1 causing their suppression and MLH1 causing their intensification. Dr. Deshmukh aims to determine how FAN1 and MLH1, which interact as a complex, can have opposing effects on CAG expansions. Understanding the role of these modifiers may help guide therapeutic targeting to delay age of onset or slow Huntington’s disease progression.

HASSAN FAkiH, PHD

Mentor: Anastasia Khvorova, PhD

Institution: University of Massachusetts Chan Medical School

Project Title: Developing nucleic acid nanoparticles for improved RNAi therapeutics to treat Huntington’s disease

Small interfering RNAs (siRNAs) are an emerging class of drugs that target disease-causing RNA for degradation in a sequence-specific manner. Such targeting is promising for hereditary diseases, where we want to deactivate (or “silence”) the disease-causing protein encoded by a specific gene. Unfortunately, siRNAs face challenges when injected into the body, as they are unstable and not delivered to their target organ/cells. However, recent advances have led to the first approvals of siRNA drugs, in this case drugs that target hereditary diseases in the liver. This success is due to the use of highly specific targeting ligands and nanoparticles capable of protecting and delivering the drug to the liver. Dr Fakih, with the Khvorova lab, plans to develop and optimize new nanoparticles capable of delivering siRNA drugs beyond the liver, specifically to the brain.

TERENCE GAll-DuNCAN, PHD

Mentor: Christopher E. Pearson, PhD

Institution: The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada

Project Title: Reversing the expansion mutation that causes Huntington’s disease

The mutation causing Huntington’s disease, a piece of DNA which repeats too many times, is very unusual. If DNA is like an instruction manual that tells our cells how to make proteins, DNA with the HD mutation is like a misprinted book with one of the pages repeated over and over and over again. When a neuron (brain cell) uses these misprinted instructions, it creates a toxic mutant protein. Dr. Gall-Duncan is characterizing and assessing a small molecule which finds misprinted repeating pages and removes them, leaving behind properly printed instructions and in effect, undoing the mutation. When HD mouse models are treated with this molecule, they become less anxious and have better motor functions. Their neurons produce fewer toxic protein clumps and other features of neurodegeneration (like DNA damage). Dr. Gall-Duncan and the Pearson laboratory believe there is therapeutic potential in this exciting small molecule.

MiCHEllE GRAy, PHD

MARiSSA

N. DEAN, MD

STEvEN PoGwizD,

MD

Institution: University of Alabama at Birmingham

Project Title: Heart problems in Huntington’s disease

There is increasing data to suggest that heart problems may exist in people with Huntington’s disease. This finding is perhaps not surprising given that the huntingtin protein is present throughout the body and in most organ systems, including the heart. However, there is scarce data on cardiac dysfunction in HD. Dr. Gray has recently shown that HD mice display deficits in the cardiac conduction system that controls the rhythm of the heartbeat. This discovery is supported by a recently published retrospective analysis of short-term electrocardiograms of people with HD that also revealed changes in the cardiac conduction system. Abnormalities included changes to the hearts’ rhythm that could leave people with Huntington’s disease susceptible to sudden cardiac arrest. Dr. Gray and her colleagues will perform further analyses of people with HD to determine the extent of cardiac abnormalities, assess in greater depth the rhythm changes, and determine whether structural changes exist.

CARoliNA GuBERT, PHD

Mentor: Anthony Hannan, PhD

Institution: The Florey Institute of Neuroscience and Mental Health University of Melbourne, Australia

Project Title: Targeting the gut bugs in Huntington’s disease: Identifying novel therapeutic opportunities

This project was inspired by increasing evidence that bugs inhabiting the gut influence brain function and dysfunction, and that the gut microbial community is abnormal in mice and people with Huntington’s disease. It has also been shown that the imbalanced gut bacterial profile observed in individuals carrying the HD gene is associated with lower cognitive performance and poorer clinical outcomes. In HD mice, Dr. Hannan’s lab recently showed that this phenomenon appears even before motor symptoms. However, they do not yet fully understand the mechanisms mediating this imbalance nor do they know whether an intervention that returns the community of bugs towards a normal profile might be therapeutic. This project will address these important questions in HD mice by using environmental, microbial and pharmacological interventions targeting the gut microbial imbalance and hopefully ameliorating brain dysfunction. This project may facilitate future development of new treatments for people with HD.

Edward Wild, PhD, FRCP University College London

National Hospital for Neurology and Neurosurgery

UCL Huntington’s Disease Centre

The hallmark of the HDF now is its brilliant ability to attract and support younger researchers, keep them in the field long enough for that to become their life’s work and then connect them with other scientists who can help them accomplish their goals.

HDF RESEARCH GRANTS

HyESEuNG lEE, PHD

Mentor: Myriam Heiman, PhD

Institution: Picower Institute for Learning and Memory

Massachusetts Institute of Technology, Cambridge

Project Title: Therapeutic targeting of Huntington’s disease with key regulators of innate immunity

In Huntington’s disease, mutant huntingtin protein ( m HTT) is expressed everywhere in the body. However, specific types of cells within the brain’s cortex and basal ganglia are more likely to die than other types of cells or than cells elsewhere in t he body. This circumstance highlights the importance of understanding how each of these different types of cells respond to mHTT. Dr. Lee and colleagues recently discovered a cell type-specific activation of innate immune signaling that they believe leads to enhanced neuronal vulnerability in HD. They hope to identify key genes that activate this immune signaling and test their therapeutic potential in Huntington’s disease.

Neurons vulnerable in HD Chang Sin Park and X. William Yang (UCLA)

RyAN liM, PHD

Institution: University of California, Irvine

Project Title: Interactions between metabolism, gene expression, and gender in Huntington’s disease

Changes in metabolism—that is, in how the cell generates energy—can affect gene expression. This interaction has been described for many disorders. However, it is unclear just how these two processes interact during disease.

Dr. Lim proposes that this interaction in the brain plays a central role in HD and that gender differences in gene expression and metabolism may result in sex-specific disease effects, a topic that has been little studied. This project investigates the inte rface between metabolism and gene expression to further understand how HD arises and progresses while exploring the possible role of gender.

JAMES MACkAy, PHD

Mentor: Lynn A. Raymond, MD, PhD, FRCPC

Institution: University of British Columbia, Vancouver, Canada

Project Title: Assessing early changes in sensory-related brain activity in Huntington’s disease

People with Huntington’s disease typically show disordered cognition and movement in middle age due to the degeneration of specific brain circuits. However, underlying HD processes begin earlier and are not completely understood. Dr. Mackay and his colleagues’ research has shown that altered sensory signals (evoked by touch, sound, etc.) spread extensively across the brain surface in HD mice and suspect that these altered brain signals could be seen with available neuro-imaging techniques in humans with HD as well. His current project aims to determine how these signals evolve with disease progression in order to validate their potential as markers of disease (biomarkers). Dr. Mackay hypothesizes that changes in the excitatory synapses (structures that mediate communication between brain cells) underlie these altered brain signals and that these changes confer vulnerability to brain cell degeneration. He aims to characterize these brain circuit changes and determine whether correcting them with drugs early in the illness can prevent neurodegeneration.

SRivATHSA MAGADi, PHD

Mentor: Walker Jackson, PhD

Institution: Linköping University, Sweden

Project Title: Modulate immune cells of the brain to alleviate Huntington’s disease

Microglia, the immune cells of the brain, have both neuroprotective and neurotoxic potential. A fine balance between these opposing capacities is disrupted in brain diseases. Dr. Magadi and colleagues found that the brains of people with Huntington’s disease produce a specific form of a ribosomal protein, Rps24, which the brains of individuals without Huntington’s do not. They hypothesize that this form of the protein is used by microglia to help the brain fight the disease. To test this hypothesis, Dr. Magadi will use cells in a dish to understand the molecular purpose of this version of the Rps24 protein. He will also use genetically engineered mouse models that enable researchers to control the production of the potentially beneficial version of Rps24 in the brain. If this form of the Rps24 protein can alter the course of the disease in mouse models , such findings can potentially be used to tailor drugs that will elicit similar effects in humans.

zACHARiAH l. MClEAN, PHD

Mentor: James F. Gusella, PhD

Institution: Massachusetts General Hospital

Harvard University, Boston

Project Title: Identifying modifiers of Huntington’s disease CAG repeat expansion and its consequent disruption of messenger RNA

The inherited expanded CAG repeat that underlies Huntington’s disease expands over time in neurons, at a rate that is modified by selected genes normally involved in repairing DNA damage. Increasing repeat length also causes HD gene (HTT) messenger RNA (mRNA) to end abruptly, which may contribute to toxicity in neurons.

Dr. McLean will construct a novel tool for selecting cultured cells with expanded or contracted CAG repeats. This tool is a system known as a reporter and is based on CAG repeat length-dependent disruption of HTT mRNA observed in patients. The reporter will be used to quantify the CAG repeat expansion rate of different patient derived alleles, which have the same length of uninterrupted CAG repeats but different DNA bases on either side. Additionally, he will undertake a screen to identify genes that modify CAG repeat instability or the disruption of HTT mRNA. Novel modifiers may provide therapeutic routes to promote CAG contraction or prevent further expansion, while modifiers of mRNA disruption may provide targets to prevent the death of neurons.

If I were to take you into my lab right now to show you the most exciting thing happening there, it wouldn’t be an experiment, it wouldn’t be a particular project - it would be the people.

Christopher E. Pearson, PhD The Hospital for Sick Children (SickKids) University of Toronto

JENNy MoRToN, PHD, SCD, FRSB

Institution: University of Cambridge, England

Project Title: Can core body temperature be used as a readout for changes in metabolism in Huntington’s disease?

It has long been suspected that changes in metabolism are important in Huntington’s disease because so many patients become very thin. But metabolism is complex and difficult to study in humans, so evidence for metabolic defects in people with HD is scarce. We know from a metabolomics study that dozens of metabolites are abnormal in presymptomatic HD sheep. In this project, Dr. Morton will use thermal imaging of sheep to see if core body temperature that is directly related to metabolism is different in HD sheep compared to normal sheep. She will then determine if temperature regulation deteriorates further in the HD sheep as the disease progresses. If this is the case, then core body temperature could be used as a non-invasive ‘surrogate’ biomarker to track metabolic changes in HD.

CHRiSToPHER NG, PHD

Mentor: David Housman, PhD

Institution: Massachusetts Institute of Technology, Cambridge

Project Title: Characterization of genetic variants that modify age of onset in Huntington’s disease

Dr. David Housman helped pioneer the 1983 discovery of the genetic marker for Huntington’s disease. The Housman lab now studies how the rest of the human genome controls the age at which a person with the Huntingtin mutation becomes symptomatic for the disease.

A postdoctoral fellow in the Housman lab, Dr. Ng plans to identify other genetic markers that modify HD age of onset. To do so he is using the extensive collection of patient samples and clinical data collected in Venezuela over a 23-year period from the world’s largest HD family. He will characterize the malfunctioning of proteins encoded by the genetic variants in HD patient samples and in mice models. Further, he aims to discover the role of modifier variants in the pathology of the disease by genetic manipulation in cells from people with HD and in HD mice models. Understanding how these variants alter the course of the disease will help distinguish the molecular pathways that are most capable of modulating Huntington’s age of onset. By going from genetic to molecular insights, he hopes to target these modifier pathways to develop protective therapies capable of slowing HD pathology.

izABEllA PENA, PHD

Mentor: Myriam Heiman, PhD

Institution: Picower Institute for Learning and Memory

Massachusetts Institute of Technology, Cambridge

Project Title: Investigating mitochondrial defects in the most vulnerable neurons in Huntington’s disease

In Huntington’s disease a specific type of neuron in the brain dies preferentially over time. This cell type is called a “medium spiny neuron” (MSN). Dr. Pena seeks to understand why MSNs are more susceptible than other neurons to the damage that unfolds in Huntington’s disease. Considerable evidence from the scientific literature suggests that there are specific defects in the mitochondria of MSNs in HD, mitochondria being one of the cell’s components (organelles) responsible for generating cellular energy. To pursue this hypothesis she will study this tiny organelle in the MSNs of mouse models with and without the HD-causing gene expansion. Dr. Pena and colleagues developed a technique that enables purification of mitochondria from MSNs and another technology that separates mitochondria from all other neurons. She seeks to understand what is specifically vulnerable about the mitochondria of MSNs in Huntington’s disease.

Neurons vulnerable in HD

Chang Sin Park and X. William Yang (UCLA)

ASHuToSH PHADTE, PHD

Mentor: Anna Pluciennik, PhD

Institution: Thomas Jefferson University, Philadelphia, PA

Project Title: O xidative damage and CAG expansions in Huntington’s disease

Huntington’s disease (HD) results from an aberrant expansion of the inherited CAG repeat tract within the huntingtin (HTT) gene. This sequence can expand further in certain cell types during the lifetime of the person with HD, and many factors can influence CAG repeat instability. The brain is an oxygen rich environment, and energy production in the brain is also accompanied with the generation of reactive oxygen species (ROS), which can cause irreversible damage to the cellular DNA. ROS-mediated oxidative damage has been observed in many neurodegenerative diseases such as Alzheimer’s, Parkinson’s and HD.

Dr. Phadte’s research will investigate the effect of ROS-mediated damage on CAG repeat instability. His study will exploit the specificity of the CRISPR-Cas9 system to promote targeted oxidative damage to the CAG repeat tract of HTT to assess CAG repeat instability under oxidative stress. Using biochemical analyses, the study will also aim to identify key proteins that assemble at sites of ROS-mediated DNA damage, further enlarging our understanding of HD pathophysiology. This work has the potential to identify new therapeutic targets against HD.

PiERE RoDRiGuEz-AliAGA, PHD

Mentor: Judith Frydman, PhD

Institution: Stanford University, Palo Alto, CA

Project Title: How disease-causing mutations in the Huntingtin protein render it toxic

The risk of developing Huntington’s disease is tightly linked with the length of a specific region within the huntingtin protein

Genetic mutations can make this region longer than normal, rendering the protein toxic to neurons. The mechanism behind this length-dependent toxicity remains unknown, mainly because the huntingtin protein’s highly disordered and aggregationprone nature prevents most current experimental methods from obtaining high-resolution images of its structures. To circumvent these technical barriers, Dr. Rodriguez-Aliaga is using a new Nobel Prize-winning technology to study one huntingtin molecule at a time, a method which allows access to structural information about pathogenic and non-pathogenic huntingtin variants with unprecedented detail.

Using this approach, he has found previously unreported structural differences between the pathogenic and non-pathogenic huntingtin variants, differences which may explain how disease-causing huntingtin mutations lead to HD. He is currently studying how huntingtin’s structure is affected by chemical modifications commonly found in brains of HD patients, and other proteins and drugs known to bind huntingtin and inhibit or decrease its toxicity.

JENNiE C. lACouR Roy, PHD

Mentor: Ricardo Mouro Pinto, PhD

Institution: Massachusetts General Hospital

Harvard Medical School, Boston

Project Title: Testing of novel drugs targeting CAG repeat expansions as potential therapeutics for Huntington’s disease

There is compelling evidence that CAG repeat expansion plays an important role in Huntington’s disease age of onset and disease progression. As a result, there is an opportunity to develop therapeutics to slow or stop expansion of these repeats and modify the disease. Dr. Roy proposes the testing of a novel drug that, in preliminary studies, has slowed the CAG expansion process in a mouse model of HD, as well as in human cells in culture. This potential therapy has promising implications for the treatment and modification of HD and, potentially, other repeat expansion disorders.

SoPHiE ST-CyR, PHD

Mentor: Beverly Davidson, PhD

Institution: Children’s Hospital of Philadelphia

University of Pennsylvania

Project Title: Understanding the underlying mechanism of the heart pathology in Huntington’s disease

Heart disease is the second most common cause of mortality in Huntington’s disease and people with HD present an increased incidence of heart failure and a smaller than normal heart. Addressing this heart pathology may improve the longevity and quality of life for people with HD. Dr. St-Cyr will explore the contribution of two RNA-binding proteins (RBPs) in HD-associated cardiac pathology. RBPs are responsible for regulating the RNA splicing of hundreds of genes, a phenomenon by which different proteins are produced from the same gene and serve different functions. CELF1 is responsible for heart splicing during development, while MBNL1 does so in adulthood. She hypothesizes that an imbalance between these two RBPs is in part responsible for HD heart pathology. To test this, Dr. St-Cyr will identify all of the RNA isoforms (protein variants) abnormally expressed in the heart of an HD mouse model and determine whether increasing MBNL1 expression ameliorates heart size and contractile function.

PARTHA S. SARkAR, PHD

Institution: University of Texas Medical Branch at Galveston

Project Title: Mechanism of mitochondrial dysfunction in Huntington’s disease

Nerve tissues isolated from people with Huntington’s disease show dysfunctional mitochondria, the powerhouses of the neurons. Mitochondria play a central role in the function of neurons because of the excess and constant energy demands of neurons. The Sarkar lab discovered that the normal huntingtin protein is important for maintaining the mitochondrial DNA integrity and that abnormal huntingtin, found in HD, disrupts mitochondrial DNA integrity. Dr. Sarkar hopes to understand the precise mechanisms by which the normal huntingtin protein maintains the mitochondrial DNA and how abnormal huntingtin disrupts mitochondrial DNA integrity and its function. Understanding these processes could potentially lead to a future therapy.

CHiARA SCARAMuzziNo, PHD

Institution: Grenoble Institut des Neurosciences, France

Project Title: Impact of mutant huntingtin on retrograde axonal routing of survival signals

Huntington’s disease is characterized by the dysfunction of the neuronal circuit between two brain regions, the cortex and striatum, leading eventually to neurodegeneration. The huntingtin (HTT) protein normally facilitates the transport of BDNF, a factor fundamental for the survival of striatal neurons and to the maintenance of synapses, the structures connecting these two brain regions. When HTT is mutated, as in HD, the transport of BDNF from the cortex to the striatum is altered, thus reducing t he survival of striatal neurons. However, the mechanisms leading to the dysfunction of cortical neurons are largely unknown. To investigate these mechanisms, Dr. Scaramuzzino reconstituted an HD brain-on-a-chip, which is a micro-chamber composed of different compartments that allows her to reproduce an HD neuronal network to study the cellular features of the disease. She then identified a new signaling mechanism by which the corticostriatal synapse conveys survival signals to the cortex. She will investigate this mechanism in HD with the objective of restoring the disrupted network. This project may lead to the identifica tion of new therapeutic approaches.

SRiDHAR SElvARAJ, PHD

Mentor: Matthew Porteus, MD, PhD

Institution: Stanford University, Palo Alto, CA

Project Title: Development of a stem-cell based therapy for Huntington’s disease

Huntington’s disease is an inherited neurodegenerative disease with no effective disease-modifying treatment. A potential therapeutic approach for HD would be to deliver protective proteins into the brain to prevent the breakdown of neurons (brain cells). Recent studies have shown that stem cell-derived neural cells have moderate therapeutic potential for HD in mouse models. Delivering protective proteins through these stem cell-derived neural cells could be a potential treatment option for humans with Huntington’s as well. In this study, Dr. Selvaraj will test the therapeutic potential of this approach for the delivery of four different protective proteins into HD mouse models. The study will provide a proof-of-concept platform for stem cell-based delivery of therapeutic proteins as a novel treatment approach for HD.

JoAN STEFFAN, PHD

Institution: University of California, Irvine

Project Title: Identification of Huntingtin-dependent cellular trash collection pathways

Dr. Steffan is investigating the normal function of the huntingtin protein in the cell’s trash collection system, a process called autophagy . Huntingtin is involved in helping to target the trash to be transported to a part of the cell, called the lysosome , where it is degraded and recycled. A small protein called ubiquitin carries the tagged trash to its destination. Dr. Steffan is examining the direct interaction between huntingtin and ubiquitin, defining the kinds of trash huntingtin scaffolds, and explor ing how this process may be impaired by the HD mutation. Through this approach, she aims to find therapies that may improve mutant huntingtin’s function and slow the progression of the disease.

ANDREw. F. TEiCH, MD, PHD

Institution: New York Brain Bank

Columbia University Irving Medical Center, NY

Project Title: Human tissue banking for the Huntington’s disease research community

The New York Brain Bank (NYBB) of Columbia University currently makes available to researchers over 1,000 carefully characterized Huntington’s disease brains as well as other human tissues. A state-of-the-art barcode inventory system, implemented by pathologist and NYBB founder Dr. Jean Paul Vonsattel, tracks the storage and disbursement of all tissue samples.

Dr. Teich aims to broaden the autopsy service to provide researchers with a greater variety of tissues, as well as scanned slides, from individuals who have died with the expanded version of the Huntington’s gene and have authorized banking of their tissue. These enriched resources will offer the research community new insights into the disease mechanisms of HD and pave the way towards better treatments and therapies for people living with HD.

RAy TRuANT, PHD

Institution: McMaster University, Hamilton, Ontario, Canada

Project Title: Imaging huntingtin at DNA sites at the atomic level

Huntington’s disease affects the way neurons (brain cells) respond to DNA damage, interfering with DNA repair and potentially triggering the events that ultimately lead to the disease. In 2017, the Truant lab visualized the recruitment of the huntingtin protein to sites of DNA damage, but huntingtin has no obvious regions known to bind DNA. So what allows huntingtin to interact with DNA, particularly at sites of DNA damage, and how might this interaction initiate HD ? It appears likely that huntingtin requires another protein, called Hap40, to bind DNA. Dr. Truant will visualize how the huntingtin/Hap40 complex directly binds to DNA and to polyADP-ribose (PAR), an important signal molecule for DNA repair that has been identified in many brain diseases. He will test various DNA shapes, as well as various types of DNA damage, comparing unexpanded and expanded huntingtin to see how the disease mutation affects the ability to bind DNA. This work will help the field understand when and how the huntingtin protein is recognizing damaged DNA and possibly how it is driving the DNA damage aspect of HD.

ANDREw S. yoo, PHD

Institution: Washington University School of Medicine, St. Louis, MO

Project Title: Increasing resilience against neurodegeneration in Huntington’s disease patient-derived neurons

Huntington’s disease is characterized by massive death of striatal medium spiny neurons (MSNs). Dr. Yoo previously found that reprogramming skin fibroblasts of people with HD to MSNs (HD-MSNs) showed adult onset pathologies, including the formation of huntingtin aggregates and cell death. Building on this work, he recently identified RCAN1 as a gene whose reduced function rescued HD-MSNs from neuronal death. However, it remains unclear how RCAN1 operates at the molecular level to promote HD-MSN degeneration. In this project, Dr. Yoo will investigate the molecular events that emerge as he reduces the function of RCAN1 and enhances HD-MSNs’ resilience in the face of neurotoxicity caused by mutant huntingtin. This work will deepen our understanding of fundamental changes in the cellular state that underlie the increased survival of patientderived neurons. He also hopes to infer strategies to keep neurons of people with HD from degenerating.

This is the Golden Age of HD research. The number of papers being published, the number of people that are now migrating to the HD field, the amount of resources, the number of companies that are finding this a desirable space - it’s unprecedented. We can make a difference in this disease. We will continue to move the ball forward, and we will not stop until we succeed.

George Yohrling, PhD Senior Director, Global Program Leader, Neuroscience Bristol Myers Squibb

Partners in Research

The Hereditary Disease Foundation’s Research Program is a worldwide collaboration among brilliant scientists pursuing treatments and cures for Huntington’s disease and related brain disorders.

The Foundation’s Scientific Advisory Board, an international group of distinguished experts, seeks out and recommends researchers pursuing bold ideas that will lead to advances and breakthroughs in scientific discovery.

Our Research Program is supported by a partnership between loyal and generous donors and HDF-funded scientists. The research we fund together can be transformative.

We thank our Partners in Research for their deep commitment to our mission and we welcome new partners to join us in pursuing game-changing scientific research that will make a powerful difference in the lives of families around the world impacted by HD and other neurodegenerative disorders. Partners in Research make a significant annual contribution to the Foundation’s Research Program and often encourage friends and family to do the same.

If you would like to discuss becoming a Partner in Research, please email Meghan Donaldson at cures@hdfoundation.org.

underwriters

Lisa and Richard Baker

Mr. and Mrs. Robert Baker

Dr. Gloria Farber

Katherine Farley and Jerry I. Speyer

The Fox Family Foundation

Benefactors

Albert Parvin Foundation

Alexander Boyd and Jane Starke Boyd Foundation

Attias Family Foundation

Barbara and Donald Jonas Family Fund

Ellin Blumenthal

John L. and Sue Ann Weinberg Foundation

Joan Leiman, PhD

Leona and Harry B. Helmsley Foundation

Peter & Dorothy A. Solomon Foundation

Collaborators

Ann and Andrew Tisch Foundation

Sean Caltabiano

Martha Darling and Gilbert S. Omenn, MD, PhD

DeVol-Fox Family Fund

Meghan and Bruce Donaldson

Sandra and Paul Montrone

Frank O. Gehry Foundation

The Lieberman Foundation

Herbert Pardes, MD

Lauren and Scott Pinkus

Anonymous

Dedee Roberts and Burton Roberts

Sarah Billinghurst Solomon

The Starr Foundation

Stephen and Myrna Greenberg

Philanthropic Fund

Betty Cooper Wallerstein

Nancy S. Wexler, PhD

Beth Ann Wheeler

Anne B. Young, MD, PhD and Stetson Ames

Anonymous

Karen and David Newman

Courtney and Jay Riffkin

The Sambado Family

Susan S. and Kenneth L. Wallach Foundation

Suzanne Wyckoff

Anonymous (2)

Listing as of December 31, 2022