Down Syndrome Therapy Advances

U.S. Researchers Pioneer Method to ‘Silence’ Extra Chromosome

WORCESTER, Mass. — Scientists have unlocked a new discovery in Down syndrome research that could lead to revolutionary new therapies and even offer hope for mothers and fathers who find out their children have Down syndrome.

Researchers at the University of Massachusetts Medical School have pioneered a way to "silence" the activity of the extra chromosome that causes Down syndrome. The discovery paves the way for new research and even opens up the possibility of "chromosomal therapies" for individuals with Down syndrome in the future.

"This is a whole new approach to understanding what goes wrong in Down syndrome cells," said Dr. Jeanne Lawrence, who led the research team at UMass Medical. "It opens up multiple avenues for research."

A human being generally has 23 pairs of chromosomes, but an individual with Down syndrome has a third chromosome in one instance, a condition called "trisomy." In the case of Down syndrome, it is an extra Chromosome 21. The extra chromosome creates a metabolic imbalance in the body that generates intellectual disability and in some cases presents physical challenges such as heart defects, leukemia and dementia later in life.

But a whole new array of research and potential therapies — even on the chromosomal level — has opened up with the groundbreaking findings of Lawrence’s team, published in the scientific journal Nature.

They found a way to shut down the activity of the extra Chromosome 21 by placing a special gene called XIST on top of it.

Normally in the human body, the XIST gene plays a vital role at the chromosome level in a female human embryo’s sexual development. While men have one X and one Y chromosome, women have two X chromosomes.

In order to prevent a metabolic imbalance from two X chromosomes, the XIST gene activates on the second X chromosome and paints it with RNA molecules, shutting down or "silencing" its metabolic activity.

By placing the XIST gene on top of the extra chromosome in a Down syndrome cell, Lawrence’s team "silenced" it, achieving de facto correction of a cell’s Down syndrome.

The study noted that this technique showed "functional correction of the underlying genetic defect in living cells is achievable," opening the way forward toward clinical gene therapy for patients with Down syndrome. It said this knowledge could even be applied to treating individuals diagnosed with Trisomy 13 and Trisomy 18, different genetic duplications that, the study noted, are "often fatal in the first one-two years."


Using Ethical Stem Cells

The researchers made use of induced pluripotent stem (iPS) cells derived from skin cells taken from patients with Down syndrome. The iPS cells have all the benefits of embryonic stem cells, but completely avoid the ethical problems surrounding the destruction of a human embryo.

Pluripotent stem-cell therapies have shown to be much more successful than embryonic stem-cell therapies, which involve the destruction of human life.

Lawrence said she has seen more scientists now interested in pursuing drug treatments and therapies for individuals with Down syndrome. She said the team’s research opens up the "most far-reaching possibility" of a therapy that could deliver the XIST gene right to the chromosomes of a person with Down syndrome.

"I thought if one could demonstrate this first obstacle could be overcome, it could generate the creativity of a number of scientists to now look at this problem," she said.

However, Lawrence said therapies from her research are still a long way off, and many more hurdles remain. The delivery mechanisms still have to be worked out, since even a harmless virus would be too small to carry the XIST gene to the affected chromosome, and many other questions remain.

"We’re going to test some of these things in mouse models to answer some of these questions," she said.

Yet, for individuals with Down syndrome (both born and unborn) and their families, the Lawrence research is setting a new benchmark for scientists looking to develop new therapies to the challenges they face.

"This is a pretty substantial step forward," said Mark Bradford, president of the Jerome Lejeune Foundation USA. The private foundation, named in honor of the discoverer of Down syndrome, Dr. Jerome Lejeune, annually funds $5 million of research and clinical trials focused on improving the lives of individuals living with Down syndrome and other genetic intellectual disabilities.

Bradford said Lawrence’s work provides scientists "a pathway to further study and investigation," but also forms part of a bigger picture about the accelerating field of Down syndrome research.

"Even five years ago, not anyone thought there would be a clinical trial in the near future," he said.

Trials of several other potential therapies are under way, perhaps the most famous contemporary example involving Swiss pharmaceutical giant Roche. It has seen promising results in a new drug called RG1662 that improves memory function.

Two clinical trials funded by the Jerome Lejeune Foundation, however, focus on the use of natural substances, which Bradford said do not carry the same danger of toxicity in human subjects as manufactured drugs do.

He said research at the Jerome Lejeune Institute in Paris has 50 infants with Down syndrome, between 6-18 months old, undergoing treatments with folinic acid and thyroid hormone. The trials so far indicate the treatment appears to aid the child’s psychomotor development, and researchers are in the process of setting up a second clinical site at a major U.S. university.

Bradford said the foundation is funding another researcher in Spain who has seen promising results from a therapy based on ECGC, an antioxidant found in green tea, which may have a positive effect on genes responsible for intellectual development.

"I would not be surprised if we did see something on the market in 10 years or so," Bradford said.

Lawrence’s research follows on the findings published in November 2012 by a University of Washington team, which also have implications for further research and potential chromosome therapies. In this case, the UW team did not "silence" the extra Chromosome 21, but eliminated it by introducing a gene called TKNEO into the targeted cells.

But advocates for individuals with Down syndrome say they are cautiously optimistic about the results of scientific research.

"Knowledge in itself is not a bad thing, but it’s what we do with it that’s challenging," said David Tolleson, executive director of the National Down Syndrome Congress. "Our technical ability often outpaces our morality."

Tolleson explained that, while parents welcome therapies to help their children live full and active lives, they are generally not interested in a "cure" that would take away their children’s Down syndrome completely or compromise their identity.

"Parents don’t want to change the essence of who their child is," added Tolleson. "But, like any parent, if you could ease some of the challenges your child might have in life, you would certainly be interested in doing that."



Generating Options

Tolleson, however, said a "positive outcome" of the Lawrence team’s research would be hopeful therapies that a doctor would recommend to a woman after a prenatal diagnosis.

Studies show that nine out of 10 women abort their unborn children when a prenatal test comes back positive for Down syndrome. The rates can be even higher for other trisomy disorders.

Bradford said new research out of Tufts University shows doctors may have a window of opportunity in the prenatal period where drug therapies could make a positive difference on the child’s development, especially in the brain.

"If we can find a way to bring these therapies to market, and provide hope in that moment, I’m sure we will be saving these babies," he said.

But even research has its moral limits. A "cure" for Down syndrome — eliminating all of a person’s extra chromosomes — would likely have to take place in the embryo stage of development, which poses serious moral barriers.

"At this point, it seems doubtful that scientists will be able to correct, in an ethically acceptable way, the extra chromosomal defect in all the cells of the body of patients with Down syndrome," said Father Tadeusz Pacholczyk, a Yale-trained neuroscientist and ethicist with the National Catholic Bioethics Center.

Father Pacholczyk explained that, while chromosome therapy in general could potentially "alleviate symptoms and difficulties" by targeting specific tissues or organs, a chromosome therapy for human embryos would likely involve risky experiments and destructive genetic testing on human embryos created in a laboratory.

"Human beings should never be engendered in laboratory glassware," Father Pacholczyk said.

Lawrence said she has always liked doing things for children with disabilities. For the past 10 years, she said, she has introduced her students to a family with a child with Down syndrome, which shows them how the child "is very loved and a wonderful member of the family."

She said these things inspired her to apply for and win the Eureka Award, a high-risk grant from the National Institute of General Medical Sciences at the National Institutes of Health, which was critical to funding her research.

"I knew this was very risky, and it might be years of effort to no avail, but if it would work, it would be important," she said. "So we decided to try."