Tag Archives: genetic disorder

Scientists reverse Down’s syndrome intellectual deficiencies in mice

Child with Down’s syndrome. Credit: Public Domain.

Individuals with Down’s syndrome — the most commonly occurring chromosomal disorder — generally have intelligence quotient (IQ) scores less than 70. They also exhibit impairments in memory and cognitive flexibility. These cognitive features are thought to be irreversible but a new study suggests that this may not be necessarily the case.

Using both genetic and pharmaceutical means, researchers at the University of California San Francisco (UCSF) showed that it is possible to reverse some of the intellectual impairments associated with Down’s syndrome in mice engineered to mimic the genetic and behavioral features of the genetic disorder.

Typically, the nucleus of each cell contains 23 pairs of chromosomes, half from each parent. However, individuals with Down’s syndrome have a full or partial extra copy of chromosome 21. Approximately one in every 700 babies in the United States is born with Down syndrome, making Down syndrome the most common chromosomal condition.

Because the disorder is genetic, most research has focused on studying how the extra chromosome disrupts normal gene activity. But in this new study, Peter Walter, professor of biochemistry and biophysics at UCSF, along with colleagues, investigated the largely overlooked role of protein synthesis and quality control in the brain, known as ‘proteostasis’.

The team first engineered mice that mimic the chromosomal, developmental, and cognitive abnormalities of Down syndrome in humans. Using polysome profiling — a technique that can image a cell’s protein production in real-time — researchers found that there was up to 39% less protein being produced in the hippocampus of the mice with Down syndrome. The hippocampus is a part of the brain that plays a key role in memory and how knowledge is obtained.

Eventually, the researchers pinned the low protein production to the activation of the integrated stress response (ISR), which is a biological circuit that protects the body when it detects something out of the ordinary — like an extra chromosome — by tamping down protein production.

In subsequent investigations on postmortem samples of brain tissue from people who had Down’s syndrome, the researchers found evidence of ISR activation there as well. This suggests that ISR is responsible at least partly for some of the cognitive effects of Down’s syndrome.

“The cell is constantly monitoring its own health. When something goes wrong, the cell responds by making less protein, which is usually a sound response to cellular stress. But you need protein synthesis for higher cognitive functions, so when protein synthesis is reduced, you get a pathology of memory formation,” said Walter. 

Walter and colleagues zoomed in on an enzyme, called PKR, which is involved in activating ISR in hippocampal cells and blocked it using three different approaches. One used a drug to suppress PKR activity, another approach involved deleting the PKR-expressing gene altogether, and the third employed an established drug called ISRIB that activates protein-production. All three approaches resulted in improvements in cognition, judging from two different memory and learning tests.

Besides behavioral improvements, the researchers also noticed improvements in synapse function in the mice after ISR activity was blocked. Additionally, the treated mice send fewer inhibitory signals that can impede learning and long-term memory.

Although the results are extremely promising, the researchers caution that this doesn’t mean that they can now suddenly reverse Down’s syndrome. There are good reasons to believe, however, that the disorder’s symptoms can be improved, which could vastly improve the quality of life of individuals living with the condition.

“We started with a situation that looked hopeless,” Walter said. “Nobody thought anything could be done. But we may have struck gold.”

The findings appeared in the journal Science.

Doctors use CRISPR technique for the first time to treat genetic disorder

A group of doctors in the United States has used the powerful gene-editing technique CRISPR to try and treat a patient suffering from a serious genetic disorder. It will take months or even years before knowing whether the treatment is safe and how well it might be helping patients, but doctors are optimistic.

Credit: Flickr


CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. The term is used to refer to the various systems that can be programmed to target specific stretches of genetic code and to edit DNA and RNA at precise locations, as well as for other purposes, such as for new diagnostic tools.

“It is just amazing how far things have come,” says Victoria Gray, who received the treatment for sickle cell disease. “I always had hoped that something will come along. It’s a good time to get healed.”

Now, researchers have used CRISPR to try and treat a disorder called sickle cell disease.

Sickle cell affects millions of people around the world, causing bone marrow to produce a defective protein that makes blood cells that are sickle-shaped. The deformed cells get stuck inside blood vessels and don’t carry oxygen normally, causing a host of debilitating and, often, eventually life-shortening complications.

“It’s horrible,” Gray said. “When you can’t walk or lift up a spoon to feed yourself, it gets really hard.”

Doctors used cells taken from patients’ own bone marrow that have been genetically modified with CRISPR to make them produce a protein that is usually only made by fetuses and by babies for a short time following birth. Now, the hope is that the protein will compensate for the defective protein that causes sickle cell disease.

“It’s exciting to see that we might be on the cusp of highly effective therapy for patients with sickle cell,” says Dr. David Altshuler, chief scientific officer at Vertex Pharmaceuticals, which conducted the study.

Gray was diagnosed with sickle cell disease when she was an infant. One major symptom is agonizing, debilitating pain. Like many sickle cell patients, her symptoms have prevented her from living a full life. She couldn’t play like other children, was afraid to travel and had to give up her dreams of becoming a doctor or a nurse.

The defective blood cells also increase the risk of infections and damage to vital organs such as the heart. They also can cause life-threatening strokes. Many people with sickle cell disease don’t live past their 40s. Gray’s heart has already suffered damage.

CRISPR enables scientists to make very precise changes in DNA, raising hopes it will lead to new ways to prevent and treat many diseases. Doctors have already started using it to try to treat cancer, mostly in China. At least two patients in the U.S. have been treated for cancer.

Later this year, doctors in Boston are planning to use CRISPR to edit cells in patients’ retinas, in hopes of restoring vision in patients with an inherited form of blindness. But there are challenges ahead.

Frangoul acknowledged there are always risks with experimental treatments. But he says the research will go very slowly and carefully with close review by the Food and Drug Administration and other advisory panels.

“We are very cautious about how we do this trial in a very systematic way to monitor the patients carefully for any complications related to the therapy,” he said.