Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Double effort against Rett's syndrome

20.12.2016

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?


The rat's brain areas stimulated in the study.

Credit: SISSA

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.

... more about:
»RNA »SISSA »nervous »nervous system »neurons

"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".

Multiple tests

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".

Media Contact

Federica Sgorbissa
pressoffice@sissa.it
39-040-374-7644

 @sissaschool

http://www.sissa.it 

Federica Sgorbissa | EurekAlert!

Further reports about: RNA SISSA nervous nervous system neurons

More articles from Health and Medicine:

nachricht Microgel powder fights infection and helps wounds heal
14.11.2018 | Michigan Technological University

nachricht Spread of deadly eye cancer halted in cells and animals
13.11.2018 | Johns Hopkins Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Massive impact crater from a kilometer-wide iron meteorite discovered in Greenland

15.11.2018 | Earth Sciences

When electric fields make spins swirl

15.11.2018 | Physics and Astronomy

Discovery of a cool super-Earth

15.11.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>