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Hunting Down Huntington's


The wheels are starting to turn on the newly formed collaboration between the Institute for Systems Biology and the Gladstone Institute of Neurological Disease's Taube-Koret Center for Huntington's Disease Research. Both institutes have set their sights on identifying potential drug targets and genes that play a role in the onset and progression of Huntington's disease, a debilitating neurological condition with no known cure. With ISB's systems biology and sequencing expertise and Gladstone's prowess in the area of neurodegenerative disease research and treatment, the two groups make a formidable team to tackle what they say is the first large-scale, whole-genome sequencing disease study of families.

"We are bringing a lot of technology, sequencing, and computational analysis to the table, and Gladstone is bringing a lot of depth through individuals who are deeply expert in various neurodegenerative diseases and several other areas that we're interested in as well," says David Galas, the senior vice president for strategic partnerships at ISB. "I think it's more computation and general systems approaches on our side and their more traditional medical and biological expertise."

According to Galas, ISB's burgeoning interest in neurodegenerative diseases helped serve as the impetus for teaming up with a partner already deep into work with extensive research models and treatment modalities for diseases like Huntington's. "Gladstone has a lot of expertise and they are a research institute of our size, so it seemed like more than a good fit, for not only this initial sequencing project with Huntington's, but also an opportunity to try and shape a broader institutional collaborative effort where there will be a number of other [disease] projects going on down the road," Galas says.

Steven Finkbeiner, associate director and senior investigator at Gladstone, says that he and his colleagues at ISB selected Huntington's to kick off the collaboration because they believe that any potential pitfalls they might run into as the project plays out could be more tractable with that disease compared to other neurodegenerative diseases such as Alzheimer's and ALS. With a large number of these diseases, the cause is unknown, and that makes moving from preclinical models to clinical trials difficult. But because Huntington's is a monogenic disease, the mouse and human induced pluripotent stem cell models are much more reliable.

If all goes well, he and his colleagues at Gladstone are confident that the technical lessons they learn from the Huntington's disease study, as well as discoveries about causes of neurodegeneration like inflammation, could translate over to other diseases. "I think all neurological diseases have certain things in common, even though obviously we don't yet understand them so we don't know how extensive the commonality is. We're hoping to begin setting up methodologies and perhaps even be able to use some of the knowledge that we gain with Huntington's to inform other genetics and systems biology research efforts in neurodegenerative disease," Finkbeiner says.

He is currently heading up the initial phase of DNA sample collection from patients with Huntington's disease and their families, including unaffected members who may be at risk for the disease. He and his colleagues will screen for potential drug targets that could delay, prevent, or even reverse the effects of the disease by using iPS cells extracted from Huntington's patients. Assisting with the collection efforts are researchers from the University of California, San Francisco, the University of California, Davis, and the Northern California Huntington's Disease Society of America, a nonprofit research group founded by Marjorie Guthrie — the widow of American folk singer Woody Guthrie, who eventually died of the disease in the late 1960s.

Crafting the collaboration

As far as the management aspects of the collaboration are concerned, Galas says that it has been a relatively easy process to arrive at an agreement with Gladstone that establishes the cost sharing. To help fund the sequencing of this project, ISB will be siphoning off some of the roughly $20 million a year it receives from the Grand Duchy of Luxembourg as part of a government effort to develop systems biology research, as well as other internal sources of funding. Further support for the sequencing effort will be provided by Complete Genomics, which assisted ISB earlier this year on another whole-genome project that identified mutations behind Miller syndrome and an inherited lung disorder called ciliary dyskinesia. On Gladstone's end, -researchers at the Taube-Koret Center are drawing on resources they can access as part of a National Institutes of Health consortium focused on using iPS cells taken from patients with Huntington's disease to create human neurons that show characteristics of Huntington's.

"The issue of how you craft a really good collaboration? That's really more of an art than a science. Our view is to start with what you need to make sure that each party has a great deal to gain from the success," Galas says. "We've tried to focus on starting small, even though this is a big project in some sense, by focusing on this one area. We're both reasonably small institutions — we're smaller than they are, so our bandwidth is not terribly high in terms of what we can do all at once. But I think that crafting these projects very carefully, focusing them and getting some early successes, is probably going to be the key."

Once the valve is fully opened on the pipeline that will connect Gladstone to ISB, the samples are sent off and the sequencing analysis gets underway, Finkbeiner says they will start to get a good sense of how to shape the clinical measures they're using into parameters that can be utilized in innovative ways with whole-genome sequencing. "I've tried to design the collection phase and the particular things I look for with the examination keeping in mind some of the studies that are going on with HD and some of the past work," Finkbeiner says.

Though, the project will evolve as it ramps up. "Now we're starting to send off samples and the sequencing is underway," he says. "As we start to get the sequencing information back … I think that's when there's going to be more give-and-take and discussion about how we can put the data we've collected in a form that will most likely reveal the sorts of connections and links that we most want to discover."

The Breakdown

Members: The Institute for Systems Biology and the Gladstone Institute of Neurological Disease Taube-Koret Center for Huntington's Disease Research
Funding: ISB and GIND will use internal funding as well as funds from their Luxembourg and NIH grants.
Time Frame: Began in early June of this year; no termination date

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