With a track record of rapid progress, the leadership of RSRT has identified three approaches to curing Rett Syndrome and embarked upon projects in each. 

There are 30,000 individual genes in the human genome. A gene may code for wavy hair or blue eyes, or susceptibility or resistance to disease. But there is another category of genes, studied in the emerging field of epigenetics.  These are the master genes which function as controllers,  switching other genes on or off in response to developmental requirements or environmental stressors to maintain normal growth and health.   Epigenetics is impacting research in everything from cancer to psychiatric disorders.
 
Mutations in a gene called MECP2 are the cause of Rett Syndrome.  MECP2 governs many other genes. Recent work suggests that it orchestrates, directly or indirectly, the activity of perhaps thousands of genes that must be properly coordinated to produce a correctly functioning brain and nervous system.  Restoration of adequate levels of MECP2 has been shown to undo the damage caused by a mutated copy of the gene. This shows us the powerful reach of MECP2's influence, as symptom after symptom disappeared in fully mature models of Rett Syndrome.
 
This astonishing preclinical breakthrough presents us with the urgent challenge of determining whether such results can be achieved in human sufferers of Rett Syndrome.  The neurobiology of Rett Syndrome is proving to be complex and  the function of the MeCP2 protein remains elusive. Basic scientists around the world remain focused on these issues.
 
As this important work progresses, there are clear approaches for intervention that must be pursued in parallel to understanding the function of MECP2.  With a track record of rapid progress, the leadership and advisors of RSRT have identified three such approaches to treating and curing Rett Syndrome.  The Trust has embarked upon projects in each of the following categories.


Increasing Levels of the MeCP2 Protein
Rett Syndrome is caused by a deficiency of MeCP2 protein. One approach to curing the disorder, therefore, is to restore normal levels. This may be accomplished in a number of ways including small molecule therapeutics (drugs) and/or biologics (gene therapy, protein replacement).
 

Some treatments may prove to be mutation specific (for example, drugs aimed at restoring normal function to an abnormally truncated protein or drugs that reconfigure misfolded proteins) while others will be more global in nature, such as activating the normal MECP2 gene on the silent X chromosome.

Gene therapy and/or protein replacement to the brain are approaches that remain quite challenging. While labs around the world make progress in overcoming the challenges in this field Rett Syndrome researchers must concentrate on identifying the specific brain regions which contribute to the many symptoms manifested in the disorder. Only once these regions are identified can gene therapy and/or protein replacement be seriously considered.

The Trust is currently funding two projects in this category. The first, in the lab of Dr. Antonio Bedalov, is aimed at activating the MECP2 gene on the silent X chromosome. The other, in the lab of Prof. Adrian Bird, is focused on correlating the specific brain regions that cause Rett symptoms. Click here to learn more about the projects.

Alleviation of specific symptoms
The array of individual symptoms in Rett Syndrome is so significant that eliminating a single one may, in many cases, dramatically improve quality of life. Finding an FDA approved drug/compound which ameliorates a symptom (such as disordered breathing, extreme anxiety, seizures) would be the quickest and most cost effective route to clinical trial.

Dr. Andrew Pieper, with RSRT support, will screen 3000 drugs and compounds in an animal model of the disease. Click here to financially support this project by "Sponsoring A Drug".

RSRT is also helping to support a project in the lab of Huda Zoghbi who is undertaking a detailed in-depth evaluation of specific FDA approved drugs. Click here to read more about projects.

Identifying target genes and genes that modify MECP2 mutations
The development of interventions aimed at genes that MECP2 controls is yet another potential avenue. Recent data, however, suggests that MECP2 may control thousands of genes. Futhermore, these genes may vary considerably depending on the tissue type. It will therefore be extremely challenging to develop treatments if thousands of genes need to be targetted. Nevertheless identifying these genes is the focus of a number of labs and progress in this are may reveal genes worth pursuing.

Perhaps a more interesting route to consider is that of MECP2 modifier genes. It is likely that differences in the genetic make-up of an individual can modulate the impact of an MECP2 mutation. There are individuals who have common MECP2 mutations and normal X chromosome inactivation but who do not have Rett Syndrome. It is likely that these individuals are protected from their MECP2 mutation due to mutation(s) in other genes. Identifying  these modifier genes could open up new avenues for treatment.

A project in the laboratory of Dr. Monica Justice is aimed at identifying MECP2 gene modifiers. Click here to learn more.

 

Banner image - Neurons from rat cortex. Nuclei with Mecp2 are purple while nuclei not expressing Mecp2 are blue.  Photography courtsey of James Eubanks.

 


 

Rett Syndrome Research Trust. © Copyright 2008