The entire extra chromosome in trisomy 21 can be inactivated in a human cell model of Down syndrome, University of Massachusetts researchers reported in a study described by leaders in the field as a “tour de force” and “extraordinary.”
Opening for the first time the possibility of chromosome therapy, rather than just single-gene therapy, the study, published in July in the journal Nature, also has immediate implications for basic research into identifying the precise genetic pathways by which trisomy 21 causes multiple effects throughout the body, researchers said.
This trial, along with other clinical trials now under way or preparing to launch with therapies aimed at improving cognition in people with Down syndrome, mark a “new day” for the field, said William C. Mobley, MD, PhD, distinguished professor and chair of neuroscience at the University of California, San Diego, as well as executive director of its Down Syndrome Center for Research and Treatment.
SILENCING THE THIRD CHROMOSOME
To silence the unwanted third chromosome that gives trisomy 21 its name, researchers led by Jeanne B. Lawrence, PhD, professor of cell and developmental biology at the University of Massachusetts Medical School, harnessed the RNA gene that normally inactivates one of the female's two X chromosome in the earliest stages of fetal development. To wrangle the chromosome-quieting power of this gene, called XIST, Dr. Lawrence's team used zinc finger nuclease technology — a means of editing the genome — to place it into one copy of the 21st chromosome. The recipient chromosome was in an induced pluripotent stem cell that was derived from fibroblast cells donated by a patient with Down syndrome.
“Researchers familiar with the XIST gene really hadn't been talking to Down syndrome researchers until now,” Dr. Lawrence told Neurology Today. “Short-term, we now have a way to study the cell pathology of Down syndrome that we didn't have before. We can take a trisomic cell, allow it to divide, place each of the cells in a separate dish, silence the third chromosome 21 in one but not the other, and then watch how they both develop. We can study neurogenesis, cardiac defects, muscle tone, and even the increased risk of developing leukemia.”
As for the prospects of using her new technique to clinically treat Down syndrome in humans, she said, “It's a long haul to do that in a person. But at least now the path can be considered. Before this, there was no path.”
Already, she is speaking with colleagues who use adeno-associated virus (AAV) to insert other genes into animal models. “We're going to try that chromosome therapy in mouse models,” she said. “One problem is that the XIST gene is bigger than what will fit into the AAV right now. But we're working on it.”
Huntington Potter, PhD, director of Alzheimer's disease programs at the University of Colorado in Denver's department of neurology and Linda Crnic Institute for Down Syndrome, called the study “an incredible breakthrough, a tour de force of bringing together many techniques that have been developed in different parts of the scientific world.”
Dr. Potter's dual role as a researcher of both Alzheimer's disease and Down syndrome highlights the interconnected nature of the two disorders: because the gene coding for amyloid-beta peptide is coded on chromosome 21, people with Down syndrome produce 50 percent more of it, and are at greatly increased risk of developing Alzheimer's disease by their early forties.
Michael M. Harpold, PhD, chief scientific officer of the Down Syndrome Research and Treatment Foundation, called the Nature study of silencing the extra chromosome 21 “spectacular” and said it demonstrates how far the field has come in the past five years.
“It's like night and day,” he said. “When our organization was founded in 2004, there wasn't much of a clue as to the mechanisms involved in the cognitive dysfunctions in Down syndrome. We now have multiple mechanisms and therapeutic targets that are being attacked. The momentum that's being built here is tremendous.”
Ira T. Lott, MD, professor emeritus and director of the Down syndrome program at the University of California, Irvine, echoed the views of others in characterizing the Nature study. “It's an extraordinary observation and a potential game changer in the way we view the biology of potential treatments for Down syndrome.”
But until such treatments become available, he emphasized, neurologists should maintain vigilance that they are adhering to current treatment guidelines.
“There are many medical complications of Down syndrome across the lifespan that can be treated or prevented,” said Dr. Lott, who is leading a study of biomarkers to identify reliable precursors to the onset of Alzheimer's disease in people with Down syndrome.
MOMENTUM FOR CLINICAL TRIALS IN DOWN SYNDROME
Along with three clinical trials now under way or preparing to launch with therapies aimed at improving cognition in people with Down syndrome, and at least two more being planned, the studies mark an exciting time to be a researcher in this field, said William C. Mobley, MD, PhD, distinguished professor and chair of neuroscience at the University of California, San Diego, as well as executive director of its Down Syndrome Center for Research and Treatment.
“Just five years ago, nothing was happening in this field,” Dr. Mobley said. “The idea of a clinical trial for Down syndrome was just this mountain that people were afraid to climb. Now it turns out you can climb this mountain.”
One of the clinical trials about to get under way seeks to lessen that risk with the investigational drug scyllo-inositol, also called ELND005. J. Patrick Kesslak, PhD, director of clinical development at Elan Pharmaceuticals, said in an e-mail that the drug has been shown to reduce amyloid levels in animal studies. The company has received approval from the Food and Drug Administration (FDA) to begin a four-week safety trial of the drug in young adults with Down syndrome without dementia.
AC Immune SA, a biopharmaceutical company based in Switzerland, is also targeting the increased risk of Alzheimer's disease among people with Down syndrome with an anti-amyloid-beta vaccine. Based on positive findings in animal models, the company hopes to begin a clinical trial of the vaccine in people with Down syndrome in the next year.
Yet another trial, already nearing completion, is a phase 1 study of the GABA-A receptor inhibitor RG 1662, developed by Roche. By suppressing the action of GABA-A, the drug was designed to relieve the excessive inhibitory signals between nerve cells that are believed to be one of the causes of cognitive disability in the disorder.
“Roche is just finishing the phase 1 trial, and they are already in talks with the FDA on phase 2 and lining up clinical sites for that,” said Roger H. Reeves, PhD, a professor in the department of physiology and the McKusick-Nathans Institute for Genetic Medicine at the Johns Hopkins University School of Medicine.
Dr. Reeves, a longtime leader in the field of Down syndrome research, said he credits the National Institute of Child Health and Human Development (NICHD) with bringing new energy to the once-moribund field.
“Yvonne Maddox, their deputy director, has been very proactive in trying to move things forward and figure out what the research agenda should be,” he said. “She's at every Down syndrome meeting, and they are now putting up the money for a Down syndrome registry that is expected to be opened later this year.”
Dr. Mobley also praised Dr. Maddox for her work. “She has run with the idea that NICHD should be one of the prominent institutes moving the field forward,” he said. “She's really making a difference.”
After years of preclinical research into the drug pentylenetetrazol, or PTZ by Craig Garner, PhD, professor and co-director of the Center for Research and Treatment of Down Syndrome at Stanford University, it too is finally being tested in an Australian clinical trial. The Cognition and Memory in People with Down Syndrome study will be a phase 1 trial.
Yet another trial, involving 200 participants in both the United States and Brazil, is being planned by Alberto Costa, MD, PhD, who recently left the University of Colorado to join the Division of Pediatric Neurology at Case Western Reserve School of Medicine in Cleveland. His phase 1 trial of the drug memantine, published last year in Translational Psychiatry, found no effect on the two primary endpoints, but did show a statistically significant effect on a secondary endpoint.
“There is more visibility in the field right now,” Dr. Costa said. “The meetings are getting more press. The idea of therapy for Down syndrome is definitely here to stay. I'm more hopeful for the future than I was a few years ago.”
Dr. Mobley made a prediction that even he conceded is bold. “In five years, people with Down syndrome will have access to drugs that make a difference,” he said.