Finding Genetic Modifiers As Avenues To Develop New Therapeutics
Drs. Nancy Wexler, David Housman, Michael Zody (The New York Genome Center), and Jean Paul Vonsattel (New York Brain Bank) are co-Principal Investigators of a groundbreaking research project funded by a $1million grant from the W. M. Keck Foundation entitled “Finding Genetic Modifiers As Avenues to Developing New Therapeutics.”
Beginning in 1979, for 23 years, a team of researchers funded by the Hereditary Disease Foundation traveled annually to Venezuela to study the world’s largest family with Huntington’s disease. The team collected important genetic and clinical information on more than 18,000 individuals. The Venezuelans’ contribution to research – including 4,000 blood samples and 100 postmortem brain tissue samples – has illuminated what is known about HD and continues to divulge new breakthroughs.
For this project, Venezuelan family members with very early and very late ages of HD onset were selected for sequencing by David Housman and Nancy Wexler. This sequencing is taking place at the New York Genome Center under the direction of Michael Zody. Sequencing allows us to discover genes, other than the HD gene, that impact the age of onset of HD.
HD can start anywhere from age 2 to 92, with typical onset between 30-40 years old. What is the genetic secret of the 92 year olds? The search for the answer is underway.
In sequencing the first group of Venezuelans, the research team discovered three genes that significantly impact the age of onset. Two of these genes produce a younger onset of disease. The third gene makes a protein that seems to be immensely protective. It delays onset, perhaps by as much as 23 years, and produces milder disease symptoms.
Because these genes work in brain cells, Jean Paul Vonsattel, Director of the New York Brain Bank at Columbia University, has sent 600 brain samples to David Housman – 100 HD brains and the rest from other brain disorders, including Parkinson's, Alzheimer's, Lou Gehrig’s (ALS) and brain cancer.
Current studies are testing the brain cells for these three recently discovered genes and other genes to learn how they work. Brains from other brain disorders are being studied to determine if they share these deleterious and protective features.
The ultimate goal is to develop therapies by isolating these protective genes. It is also important to study the two genes that accelerate HD onset so that more can be learned about therapies that can block their harmful effects.
This is a unique opportunity to launch the biggest potential breakthrough to develop new treatments and cures for HD and other brain disorders.
“Important discoveries often start small, but seeding key ideas with funds to start exploring can have a huge impact on outcomes. In 1983, the W. M. Keck Foundation began collaborating with the Hereditary Disease Foundation…with the saga of a group of gene hunters determined to track down the cause of this devastating disease and find a cure…Thanks to four Keck Foundation grants to HDF, the gene responsible for HD has been located and the search for a cure is under way.”
The W. M. Keck Foundation Annual Report