Currently Funded Research

“Finding Genetic Modifiers As Avenues to Developing New Therapeutics”

Nancy S. Wexler, Ph.D.
Hereditary Disease Foundation, Columbia University

David Housman, Ph.D. 

Robert Darnell, M.D., Ph.D. 
New York Genome Center

Jean Paul Vonsattel, M.D. 
New York Brain Bank

The Hereditary Disease Foundation’s groundbreaking research on genetic modifiers, made possible by a grant of $1,000,000 from the W. M. Keck Foundation, is moving forward at the New York Genome Center. The goal of this project is to understand why the ages of onset of Huntington’s disease are so varied. By knowing what controls the onset of the disease, we hope to find a way to delay its onset.

To do this, the HDF is performing in-depth analyses of brain tissues and DNA from blood samples, utilizing two decades of data collected from the HDF’s research collaboration with Venezuelan families suffering from Huntington’s . For this project we have specifically selected genetic material from 250 family members who were stricken with HD either when very young or very old.

We see great promise — particularly for drug development – in what we will glean from these sequencing studies.

Other highlights of current research funded by the HDF include:

Marie-Francoise Chesselet, M.D., Ph.D.

David Geffen School of Medicine at UCLA

Project Title: Preclinical evaluation of D-PUFAs as a therapeutic intervention for HD

Marie-Francoise Chesselet, a long-time HDF SAB member, was recently awarded HDF funding to test compounds (known as D-PUFAs) in mice for their ability to protect brain cells from HD damage. D-PUFAs are of interest because they reduce an alteration observed in cells affected by HD. Moreover, they have been given to humans in many studies with no apparent ill effects. If the results of Dr. Chesselet’s experiments are positive, the compounds could be tested relatively quickly as a dietary supplement in humans.


Yoon H. Cho, Ph.D.

Associate Professor, University of Bordeaux

Project Title: Sleep as a window for a therapeutic clue against Huntington’s disease

People with Huntington’s disease often have difficulty sleeping. Mice which have been genetically modified to have the HD gene sleep as poorly as humans with HD do. Recording the brain activity of these mice while they slept, using an electroencephalographic (EEG) technique, Yoon Cho and her team discovered a strange brain activity. This was caused by a large number of neurons firing abnormally in synchrony. This activity was not present at all in normal mice. To understand where in the brain this activity was coming from, Dr. Cho and her group first tried to modulate this abnormal activity with drugs that modulate sleep and wake cycles. They found that a new sleeping pill significantly improved the HD mice’s aberrant brain activity and other sleep disturbances. The pill, which blocks the chemical activity of orexin, is important for maintaining our wakefulness.

Cho’s current project, funded by the Hereditary Disease Foundation, is testing if the sleeping drug also corrects behavioral and cognitive impairments in these HD mice as it did the atypical brain activity and sleep disturbances. Because the drug is already available in the U.S. and Japan, this work, if validated, could lead very rapidly to a clinical trial targeting the alleviation of symptoms of Huntington’s disease.


Pan Li, Ph.D.

Research Associate, MENTOR: Russell Margolis, M.D., Johns Hopkins University

Project Title: A high throughput screen for small molecules enhancing the expression of HTTAS-a novel therapeutic strategy for HD

Russell Margolis’ group recently identified a piece of RNA (the recipe for making proteins) that is widely expressed at low levels in the brain. When this RNA is overexpressed, it lowers the amount of the protein that causes HD. They hypothesize that this RNA will provide novel therapeutic targets for suppression of the abnormal HD protein and, therefore, will be an effective treatment of HD.

Funded by the Hereditary Disease Foundation, this current research will explore the mechanism and magnitude of the effect this RNA has on the expression of the HD protein. They will use skin cells and stem cells of HD to quantify their findings. Their strategy provides an alternative approach to suppress the HD-causing protein, which may have considerable therapeutic potential. 


Christian Neri, Ph.D.

INSERM, Paris, France

Project Title: Modeling the role of extracellular vesicles in HD pathogenesis

Christian Neri received HDF funding for a project that extends his lab’s seminal research on how cell’s ability to cope with stress is altered very early on in HD. In his new project, Dr. Neri will examine the function and cargo of tiny sacs (known as exosomes) which can carry stress-signaling molecules to cells in different locations. The project is expected to identify a new mechanism that could lead to new therapies to protect key areas of the brain affected by HD. The studies may also lead to the discovery of new markers useful for monitoring the effects of other drugs designed to regulate stress responses.

Ai Yamamoto.jpg

Ai Yamamoto, Ph.D.

Assistant Professor, Columbia University

Project Title: ALFY-mediated Degradation and HD

Ai Yamamoto was recently awarded Hereditary Disease Foundation funding to better understand how brain cells are able to remove abnormal huntingtin, the protein that causes damage in HD. Her focus is a protein called Alfy that helps to package up and dispose of clumps of harmful litter in the brain. In HD animal models, clearing away abnormal huntingtin deposits has led to improvements in symptoms, and Alfy plays an important role in cleanup. This project aims to closely examine the huntingtin removal process by lowering or boosting levels of Alfy in HD mouse models, and testing how it affects their behavior. A better understanding of Alfy’s function could help to identify therapeutic approaches to speed the elimination of damaging debris in HD brain cells.