The trick against haploinsufficiencies: Getting the 'single' gene to work for 2
Imagine that a colleague of yours has fallen ill and will be absent for a while from the office. What do you do? Do you go on working at your usual pace and by doing so risk a huge backlog of work that will affect the performance of the whole office, or do you roll up your sleeves and get down to it (perhaps also after your boss has motivated you by promising some benefit) by doubling your efforts and doing your absent colleague's work as well as your own?
Something similar occurs with genes when their homologues are missing, a condition doctors call haploinsufficiency. When this abnormality manifests, especially when it concerns genes that have an important function in the central nervous system, it may lead to very serious diseases, such as Rett's syndrome that causes severe progressive mental retardation related to the FOXG1 gene.
A group of researchers at the International School for Advanced Studies (SISSA) in Trieste, led by Antonello Mallamaci, has decided to adopt the "motivational" boss strategy by stimulating the surviving FOXG1 gene to work more to compensate for the absence of the missing gene.
"By using viral vectors to insert into neurons RNA fragments targeting the gene's regulatory sequences, we "gently" stimulated the gene to do more work, in particular nearly double", explains Mallamaci. "Note that we don't want the gene to do more than that. If it worked, say, three times as much, it could cause even worse damage". In fact, it is known that when three copies of the FOXG1 exist (one more than normal), we have West's syndrome, which is perhaps even worse as it causes a severe form of epilepsy. "It's therefore vital that the gene we stimulate does no more than about double the normal amount of work".
The method adopted by the Trieste group is a "cunning" solution to the treatment problems posed by these diseases. "Stimulating the normal gene allows us to preserve its natural endogenous regulation", explains Mallamaci. Genes in fact are not expressed everywhere and at the same intensity: to the contrary, in many body tissues they are silenced, in others their activity is time-modulated with great precision. If their regulation were to be disrupted, it is easy to imagine the chaos that this would generate. "Going back to the office worker's metaphor, it's like having an inexperienced intern do the absent worker's job: at best he won't do anything, at worst he'll mess things up. Instead, asking an experienced colleague, who's familiar with the office's processes and rhythms, to work harder, offers greater guarantees".
The team ran several tests. First, in vitro, the scientists checked whether stimulation through promoter RNA was able to amplify gene activity only where it was needed. "FOXG1 is only active in the anterior brain and we absolutely don't want it to act elsewhere in the nervous system or the body", explains Mallamaci. "The tests gave positive results: after stimulation, the gene continued to be expressed only in cells where it had previously been active and remained silent in tissues where it normally doesn't work. Very importantly, the activity observed increased by a factor not far from 2, i.e. that "double" expression that we were trying to achieve".
The second test, also in vitro, demonstrated that the gene's endogenous regulatory mechanisms related to the electrical activity of the neurons expressing it are not altered by stimulation with RNA: "we saw a rise in the gene's activity, but the shape of the time-activity curve was basically unchanged, a clear indication that regulation remains the same", explains Cristina Fimiani, PhD student in Functional and Structural Genomics at SISSA and co-first author of the study.
The third step was to see whether the stimulation also worked in vivo. "The test was done on healthy mice and we found that the stimulation was even more effective in vivo than in vitro," Mallamaci concludes.
"We're still at the beginning of a very long clinical process that might one day lead to treatment", he adds. "The results, though, are very clear and definitely encourage us to continue this line of research. The next steps will be in vivo tests on animal models affected by the disease".
What makes these therapies so interesting for the future? "Rett's disease is rare and affects only a small number of patients, so it doesn't attract the attention and investments of major pharmaceutical companies", concludes the scientist. "But, taken together, haploinsufficiencies affect very many people. The methodology we present in this study is therefore a test for a general method capable of fighting the large number of haploinsufficencies affecting the nervous system, and once developed it could be easily adapted to different genes".
Federica Sgorbissa | EurekAlert!
Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn
Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
20.10.2017 | Interdisciplinary Research
20.10.2017 | Materials Sciences
20.10.2017 | Earth Sciences