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Hereditary Disease Foundation Supports and Catalyzes Critical Achievements Toward the Cure

1968 - Milton Wexler forms the Hereditary Disease Foundation after his wife and all of her three brothers are stricken with Huntington's disease. The Hereditary Disease Foundation begins its pioneering role in spearheading innovations in modern molecular genetics.

1979 - Nancy Wexler initiates the U.S.-Venezuela Huntington's Disease Collaborative Research Project, an ongoing study of the world's largest HD community living along the shores of Lake Maracaibo. This work is the longest and largest prospective, longitudinal study of HD worldwide. The Venezuela kindred has over 18,000 people, most from one extended family originating in the early 1800s.

1983 - James Gusella, Harvard University; Nancy Wexler; P. Michael Conneally, Indiana University; David Housman, MIT; and others discover the general location of the Huntington's disease gene near the top of chromosome four. This is the first time that a gene is located using DNA markers when its address on a chromosome is completely unknown. Our success, heralded around the world, proved that these techniques could work for finding genes, and was a critical launching pad for the Human Genome Project - called "the most important scientific undertaking of our time."

1993 - The Huntington's Disease Collaborative Research Group, an international consortium of over 100 investigators led by the Hereditary Disease Foundation, isolates the actual Huntington's disease gene on chromosome four, identifying the mutation as an expanded trinucleotide repeat. During its ten-year search for the gene, the Group develops 14 new technologies used in subsequent investigations to find disease genes. It also provides a powerful new model for collaborative biomedical research.

1995 - Scott Zeitlin and Argiris Efstratiadis, Columbia University, create the first HD "Knock-Out" mouse - removing the mouse's own version of the Huntington's disease gene, almost identical to its human counterpart. They reveal that the HD gene performs an essential function for life.

1996 - Gillian Bates, Guy's Hospital, London, UK, develops the first transgenic mouse model of Huntington's disease by placing a portion of the human HD gene in a mouse, providing an invaluable and continuing goldmine of information about HD.

1997 - Gillian Bates and Stephen Davies, University College London, UK, discover aggregates of the HD protein in the nuclei of HD mice, leading to the discovery of these same aggregates in humans with HD.

1997 - The Hereditary Disease Foundation launches the Cure Huntington's Disease Initiative to accelerate progress from research to therapy. The strategy aims to stimulate and coordinate research in both academia and private industry.

1998 - George Jackson and S. Lawrence Zipursky, UCLA, create the first fruit fly (Drosophila) model of HD.

1998 - James Olson, Fred Hutchinson Cancer Research Center, forms the Huntington's Disease Array Group, comprised of 50 investigators from eight labs in the US and Canada. The Group uses microarray chips in animal models and in human tissue to search for genes "turned on or off" in HD. The Group's findings initiate a therapeutic drug trial in mice.

1999 - M. Flint Beal, Weill Medical College of Cornell University, establishes the first Mouse House, a facility for testing potential drug candidates in several different HD mouse models.

1999 - Jenny Morton, University of Cambridge, UK, begins a large project assessing the therapeutic effects of different drugs on behavior, symptoms and longevity of HD mice.

1999 - Robert Friedlander, Harvard University, treats HD mice with an experimental therapy resulting in the first improvement of symptoms.

1999 - Paul Patterson, Caltech, creates monoclonal antibodies, named after Hereditary Disease Foundation founder Milton Wexler, that reveal new properties of the huntingtin protein.

1999 - William Yang, UCLA, and C.J. Li, Weill Medical College of Cornell University, create the first transgenic mice which contain a piece of bacterial artificial chromosome (BAC). The HD gene can be targeted to precise areas of the mouse brain, revealing much about intricate brain circuitry damaged by the HD protein.

2000 - Peter Detloff, University of Alabama, Birmingham, creates a "Knock-In" mouse with a huge expansion that causes severe HD symptoms and early onset.

2000 - Ai Yamamoto and Renˇ Hen, Columbia University, and Josˇ Lucas, Center for Molecular Biology, Madrid, Spain, produce the first reversal of symptoms in an HD mouse. The human HD gene is placed in a mouse with a special genetically engineered "switch" that can be turned off long after symptoms appear. When no longer exposed to HD's "poisonous protein," the mouse's brain cures itself!

2001 - HDF provides funding for research aimed at developing RNA interference(RNAi)-based treatments for HD.

2002 - HDF holds its first workshop on RNAi-based treatments for HD with leading experts in the field, including 2006 Nobel laureates Andrew Z. Fire, Stanford University School of Medicine, and Craig C. Mello, University of Massachusetts Medical School, co-discoverers of RNAi.

2002 - Leslie Thompson, Joan Steffan and Lawrence Marsh, UC, Irvine, demonstrate that drugs called histone deacetylase (HDAC) inhibitors reverse the degeneration of neurons and prevent early death in their fruit fl y (Drosophila) model of HD.

2002 - The Hereditary Disease Foundation initiates a "virtual company" of drug screening. These include primary, secondary and tertiary screens - from cells and yeast to worms, flies and mice. HDF supports screening of all FDA-approved drugs as well as additional "libraries."

2003 - Gillian Bates shows that suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor, dramatically improves the movement impairment in a mouse model of HD.

2003 - Beverly Davidson and Henry Paulsen, University of Iowa, and Neil Aronin and Phillip Zamore, University of Massachusetts, discover new ways of selectively "turning off" the HD protein, leaving the normal protein intact and functional using RNAi. These discoveries are virtual cures for HD if they can be transferred to the brain!

2004 - Nancy Wexler and the U.S.-Venezuela Collaborative Research Project show that the age at which HD starts is not determined solely by the HD gene, as previously believed, but is strongly influenced by genes other than the HD gene and by environmental factors.

2005 - Beverly Davidson publishes groundbreaking research on RNAi therapy for HD, showing that delivery of RNAi to the brain of mice expressing the mutant HD gene has a significant beneficial impact on the symptoms and progression of the disease.

2005 - William Yang generates mouse models which show, for the first time, that a large fraction of the neuronal toxicity observed in HD may be caused by toxic cell-to-cell interactions between neighboring cells.

2005 - Steven Finkbeiner, UC, San Francisco, uses a microscope to elucidate which forms of mutant huntingtin are most poisonous, which could reveal how mutant huntingtin causes degeneration and may lead to specific therapies that block it.

2006 - Beverly Davidson and Krystof Bankiewicz, UC, San Francisco, begin developing methods for delivering RNAi-based therapy to the brain and testing the safety in animal models of an RNAi-based therapeutic product being developed for HD.

2006 - David Housman and Ruth Bodner, MIT, together with Aleksey Kazantsev and Bradley Hyman, Harvard University, identify a compound that interferes with the pathogenic effects of HD, which could lead to development of new treatments for the disease.

2006 - Michael Hayden and colleagues, Centre for Molecular Medicine and Therapeutics, Vancouver, Canada, discover that by preventing the cleavage of the mutant huntingtin protein responsible for HD in a mouse model, the degenerative symptoms underlying the illness do not appear and the mouse displays normal brain function. This is the first time that a cure for HD in mice has been successfully achieved.

2006 - William Yang generates a bacterial artificial chromosome (BAC) transgenic mouse model with the full-length mutant human HD gene inserted into the mouse genome. The study reveals that BACHD mice exhibit progressive and robust behavioral and neuropathological phenotypes that closely match that of the human disease. This model is also the first full-length mutant HD gene model in which expression of the toxic protein can be switched off in different cells, making it an ideal model to study cell-to-cell interactions in HD.

2007 - Robert Hughes, Buck Institute for Age Research, and colleagues identify more than 200 new proteins that bind to normal and mutant forms of the protein that causes HD. These proteins are modifier genes which lessen or increase the severity of Huntington's disease or advance or delay onset.

Some of the many Venezuelans at risk for HD whose donations of DNA samples helped find the gene

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