Researchers at the Buck Institute fixed the genetic mutation that causes Huntington’s Disease, raising hopes of eventually reversing and curing the inherited brain-wasting disease in humans.
The work, using induced pluripotent stem cells in the lab of Lisa Ellerby at the Buck Institute for Research on Aging in Novato, is early stage and currently is using mice. The therapy has not been tested in humans, and the lab continues to see if mice transplanted with corrected cells have functional improvements.
But in a paper published online Thursday in the journal Cell Stem Cell, Ellerby’s lab details how it used reverse-engineered cells from a Huntington’s patient, made a genetic correction and generated fresh neural stem cells. When the disease-free cells were transplanted into mice, the animals generated normal neurons in the area of the brain affected by Huntington’s.
“The thing that’s really neat about this in any disease (is) you really are correcting the mutation,” Ellerby said. “You’re fixing the problem.”
Induced pluripotent stem cells are mature stem cells, like skin, that can be manipulated in the lab to act like embryonic stem cells and then be coaxed to form various cell types. Many scientists have seen so-called IPS cells as a way to screen drugs and study how diseases work, especially considering the moral and political roadblocks around destroying embryos for embryonic stem cell research.
But Ellerby’s lab takes that one step further, pushing IPS cells where others have long seen them, into the realm of personalized medicine. Huntington’s patients, for example, eventually could have their own “designer” cells cleansed, banked and transplanted for a personalized cure.
“They could be put into anybody … but then you may get an immune rejection and maybe issues we don’t know about yet,” Ellerby said about transferring cells between patients. “This is just a very clean way.”
Three to seven of every 100,000 people of European ancestry get Huntington's Disease, according to the U.S. National Library of Medicine.
Although Huntington’s march through the brain is thought to be determined during embryonic development, patients typically don’t have symptoms until their mid-30s or 40s. Those symptoms range from irritability to slow, uncontrolled movements, memory loss, disorientation and slurred speech.
Patients, who typically lose about 2 percent of the neural cells over 10-15 years, often die within 20 years after the onset of symptoms.
There is no cure, but patients typically receive drugs like dopamine to slow symptoms or control movements. Research also has picked up because, unlike Alzheimer’s Disease and Parkinson’s Disease, the cause has been pinpointed as a single genetic mutation.
The Gladstone Institutes in San Francisco, for example, earmarked a $3.6 million gift in 2009 from Taube Philanthropies and the Koret Foundation for a Huntington’s research center. In fact, a team of international researchers, including those from the Gladstone, also published a paper Thursday in Cell Stem Cell around their creation of a human model for Huntington's disease directly from the skin cells of patients with the disease.
More often than not, however, potential therapies have failed to make it through the drug-development process. A Phase III trial last year by San Francisco’s Medivation Inc.’s failed.
The Huntington’s defect, discovered in 1993, causes a part of DNA that normally is replicated 10 to 28 times to replicate 36 to 120 times. Ellerby’s team can take patients with 72 “repeats” to about 20.
Ellerby’s team started working on the project about three years ago and now is able to convert cells in about two to three months using a process known as “homologous recombination.” That method exchanges bad DNA with good DNA.
Correcting the disease in a lab dish is difficult enough; getting the corrected cells to generate over and over again has been a more difficult problem. Neural stem cell researchers, in particular, have been tripped up in getting the cells to regenerate in the brain or spinal cord.
Ellerby’s lab, however, saw corrected cells in Huntington’s-affected mice populate parts of the brain affected by the disease.
“It’s really exciting,” Ellerby said.
The work was funded by the Buck Institute and the National Institutes of Health. The California Institute for Regenerative Medicine, the state’s $3 billion, bond-supported stem cell research funding agency, did not fund the work.
Along with Ellerby, other researchers in the study were Mahru An, Ningzhe Zhang, Gary Scott, Daniel Montoro, Tobias Wittkop, Sean Mooney and Simon Melov.
“I don’t feel we’re ready to move into HD patients,” Ellerby said, noting her team's ongoing studies to discover if the new neural cells actually help Huntington's patients improve. “When you use mouse models, the goal is to go into patients. But does it work? Is it safe? How can it be optimized to work the best way it can?”