Gene Tied to Down Syndrome May Suggest Way to New Therapy

by Nicole Ostrow from Bloomberg:
Scientists have identified a gene on the extra chromosome causing Down syndrome that may be responsible for the early aging and cognitive defects in people with the condition, a finding that could lead to new treatments.
The gene, called Usp16, may hinder the body’s ability to make stem cells needed to maintain tissues and organs, according to research published today in the journal Nature. That includes development of organs such as the brain while in the uterus, said Michael Clarke, a senior study author.
The findings in mice and human cells are the first to help explain why people with Down syndrome show signs of early Alzheimer’s disease and age faster, the authors said. Further investigation may test whether the gene might slow down these aging effects or fight against other diseases like Alzheimer’s and cancer, Clarke said.
“Like most regulators and stem cell functions, understanding how those things work has potential implications in a wide range of diseases,” Clarke, a professor of medicine at Stanford University near Palo Alto, California, said in a telephone interview. “Now that we have a pathway, there might be drugs that could be used to improve some of the problems.”

How Down syndrome may help unravel Alzheimer's puzzle

by Linda Carroll from NBC NEWS Today:
Scientists have known for decades that people with Down syndrome were at increased risk of developing Alzheimer’s disease, but they didn’t know why. Some researchers now believe that understanding the connection between the two conditions might help us unravel the Alzheimer’s puzzle and point towards therapies that might slow, or even halt, the dreaded disease.

Visit NBCNews.com for breaking news, world news, and news about the economy

“It’s a tantalizing and provocative question: Do people with Down syndrome hold the key to the mystery of Alzheimer’s development?” Dr. Brian Skotko, co-director of the Down Syndrome Program at the Massachusetts General Hospital in Boston, said in a telephone interview. “And what can we learn from those with Down syndrome that will benefit the rest of the population?”

The link between Alzheimer's disease and Down syndrome

by Maureen Wallace from She Know's: Parenting:
Throughout my life, I've feared I would one day develop Alzheimer's disease. I never expected I'd have a child with Down syndrome whose chances of developing Alzheimer's (AD) surpassed mine.

Individuals with Down syndrome have increased risk of developing Alzheimer's disease and related dementia. The idea terrifies me. If I'm worried I won't be able to take care of myself in my old age, what makes me think I will be able to care for my son?
My 3-year-old son, Charlie, has Down syndrome (Ds), which means while most people have 46 chromosomes, he has 47 — thanks to a third copy of the 21st chromosome.
The 21st chromosome. Remember that.

In a laboratory dish, researchers shut down extra chromosome that causes Down syndrome

by Carolyn Y. Johnson from The Boston Globe:

Researchers at the University of Massachusetts Medical School have shown that it is possible to do what had once seemed unthinkable—shut down the extra chromosome that causes the developmental problems and intellectual disabilities in people with Down syndrome.

The surprising result—so far accomplished only with human cells grown in laboratory dishes—is the fruit of a daring, out-of-the-box approach by a scientist whose work has been shaped by her early experience counseling families of children with disabilities.

“It really is revolutionary, in terms of causing us all to rethink the one impossible thought—can you make, functionally, that extra chromosome disappear,” said Dr. Brian Skotko, co-director of the Down Syndrome Program at Massachusetts General Hospital, who was not involved in the new study. “I don’t think any of us thought it was possible or even within the current realm of scientific dreaming that we might one day be able to do it.”

New genetic cause for learning disability in Down syndrome identitfied

Neurons from a normal mouse (left) are longer and fuller than neurons from a mouse lacking SNX27 (right).

By Dr. Leila Luheshi from PHG Foundation:

Researchers have reported a novel molecular mechanism through which triplication of chromosome 21 could cause deficits in learning and memory in patients with Down syndrome.
Down syndrome is caused by the abnormal inheritance of three (rather than the usual two) copies of chromosome 21.  At a genetic level this leads to higher than normal levels of expression of the many genes and non-coding RNAs that are encoded on this chromosome.  Clinically this results in a complex constellation of symptoms of which the most prominent is a varying degree of learning disability.  Learning disability in Down syndrome is associated with reductions in the number and activity of the synapses (connections) made between neurons in the brain, and so understanding the mechanisms underlying these neurodevelopmental abnormalities may provide the key to ameliorating the effects of this disorder.

A new study in Nature Medicine reports that the protein encoded by the sorting nexin 27 (SNX27) gene, which is present at abnormally low levels in the brain of patients with Down syndrome, may underlie the presence of learning disabilities in this condition. 

The researchers showed, by knocking out the Snx27 gene in mice, that its expression is vital for brain development.  In particular they discovered that Snx27 is vital for the maintenance of synaptic activity and consequently for learning and memory, deficits in which underlie learning disability in patients with Down syndrome.  In a key experiment that linked these observations in mice more directly with the symptoms of Down syndrome in humans, the team were able to demonstrate that increasing Snx27 levels in a mouse model of Down syndrome could reverse the learning and memory deficits from which it is suffers.  

Extra chromosome 21 removed from Down syndrome cell line

By Leila Gray from UW Health Sciences/UW Medicine:

University of Washington scientists have succeeded in removing the extra copy of chromosome 21 in cell cultures derived from a person with Down syndrome, a condition in which the body’s cells contain three copies of chromosome 21 rather than the usual pair.A triplicate of any chromosome is a serious genetic abnormality called a trisomy. Trisomies account for almost one-quarter of pregnancy loss from spontaneous miscarriages, according to the research team. Besides Down syndrome (trisomy 21), some other human trisomies are extra Y or X chromosomes, and Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13), both of which have extremely high newborn fatality rates.
In their report appearing in the Nov. 2 edition of Cell Stem Cell, a team led by Dr. Li B. Li of the UW Department of Medicine described how they corrected trisomy 21 in human cell lines they grew in the lab.  The senior scientists on the project were gene therapy researchers Dr. David W. Russell, professor of medicine and biochemistry, and Dr. Thalia Papayannopoulou, professor of medicine.
The targeted removal of a human trisomy, they noted, could have both clinical and research applications.
In live births, Down syndrome is the most frequent trisomy. The condition has characteristic eye, facial and hand features, and can cause many medical problems, including heart defects, impaired intellect, premature aging and dementia, and certain forms of leukemia, a type of blood cancer.
“We are certainly not proposing that the method we describe would lead to a treatment for Down syndrome,” Russell said.  “What we are looking at is the possibility that medical scientists could create cell therapies for some of the blood-forming disorders that accompany Down syndrome.”
For example, he said, someday Down syndrome leukemia patients might have stem cells derived their own cells, and have the trisomy corrected in these lab-cultured cells.  They could then receive a transplant of their own stem cells – minus the extra chromosome – or healthy blood cells created from their fixed stem cells and that therefore don’t promote leukemia, as part of their cancer care.
He added that the ability to generate stem cells with and without trisomy 21 from the same person could lead to better understanding of how problems tied to Down syndrome originate.  The cell lines would be genetically identical, except for the extra chromosome. Researcher could contrast, for example how the two cell lines formed brain nerve cells, to learn the effects of trisomy 21 on neuron development, which might offer insights into the lifelong cognitive impairments and adulthood mental decline of Down syndrome. Similar comparative approaches could seek the underpinnings of untimely aging or defective heart tissue in this genetic condition.
The formation of trisomies is also a problem in regenerative medicine research using stem cells. Russell and his team observed that their approach could also be used to revert the unwanted trisomies that often arise in creating stem cell cultures.
Figuring out the exact techniques for removing the extra chromosome was tricky, Russell said, but his colleague Li worked hard to solve several challenges during his first attempts at deriving the engineered cell lines.
“Dr. Li’s achievement was a tour de force,” Russell said.
The researchers used an adeno-associated virus as a vehicle to deliver a foreign gene called TKNEO into a particular spot on chromosome 21, precisely within a gene called APP, which sits on the long arm of the chromosome.  The TKNEO transgene was chosen because of its predicted response to positive and negative selection in specific laboratory growth mediums.  When grown in conditions that selected against TKNEO, the most common reason for cells to survive was the spontaneous loss of the chromosome 21 harboring the transferred gene. Other survival tactics were point mutations, which are single, tiny alterations in DNA base pairs; gene silencing, which meant TKNEO was “turned off” by the cell; or deletion of the TKNEO.
Russell explained a key advantage of this technique for getting rid of the entire extra chromosome: Once it was gone, nothing was left behind.
“Gene therapy researchers have to be careful that their approaches do not cause gene toxicity,” he said. This means, for example, that removal of a chromosome must not break or rearrange the remaining genetic code. This method shouldn’t do that.”
Other researchers on this study were Kai-Hsin Chang, Pei-Rong Wang and Roli K. Hirata. The project was supported by grants from Horizon Discovery and from the National Institutes of Health (DK55759, HL53750,GM086497, DK077864, and HL46557.)  The researchers declared no financial conflicts of interest.