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).

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.

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