Gene Modifying Therapy Research: Accelerating Toward a Cure

Gene Modifying Therapy Research: Accelerating Toward a Cure

Categories: Blog, Homepage, Research

By Dominique Pichard, MD, Chief Science Officer,

We wanted to explain this incredibly complicated work and at the same time let you know that we’ve got you covered.

We are working hard to provide a better life for your loved ones with Rett syndrome. It is believed that the greatest life improvements will come from treatments that address Rett syndrome at its root cause: mutations in the Methyl-CpG Binding Protein 2 (MECP2) gene. Gene modifying therapies, a class of treatments that work by altering genes inside the body’s cells, may do just that. By fixing the MECP2 defect, these treatments could permanently convert the diseased cells of a patient with Rett syndrome into healthy ones. Hopefully, this would stop disease progression, eliminate symptoms, and possibly provide a curative therapy for Rett syndrome. Today, gene modifying therapies are becoming a reality. Many in our community may be aware of the recent success of a Spinal Muscular Atrophy (SMA) gene therapy.

This therapy overcame one of the major barriers to Rett syndrome gene modifying therapy: delivering genetic changes to brain cells. This achievement brings us much closer to a gene modifying therapy for Rett syndrome. Yet, much work remains to be done to ensure the safety and efficacy of such a treatment. We still don’t know the consequences of modifying a patient’s mutant MECP2 gene. Additionally, we know that while MECP2 mutations cause Rett syndrome, too much good MECP2 can result in another disorder. Thus, modifying MECP2 requires great care.

Fortunately, there are many ways to approach gene modifying therapy, including gene replacement (the method used to treat SMA), gene activation, and RNA editing. currently funds research on all these approaches.

Gene replacement provides a working MECP2

One way to treat Rett syndrome is to simply give cells a working copy of MECP2. Gene replacement accomplishes this task using an adeno-associated virus (AAV) vector. This non-pathogenic AAV vector functions as a delivery service. It travels from the site of its injection to the cells in the brain where it adds its normal MECP2 gene “package” to these cells’ contents, providing a replacement for the mutant MECP2.

Before this type of therapy can be attempted in humans, it must be thoroughly tested in an animal model. Toward this end, Dr. Steven Gray at UT Southwestern, one of our previously funded researchers, has helped develop AAV vectors for thedelivery of MECP2 in mouse models of Rett syndrome. Some of our currently funded researchers are also making advancements in this space, including Dr. Sarah Sinnett, a next-generation researcher and former post-doctoral researcher in Dr. Gray’s lab. Dr. Sinnett at UT Southwestern is working to find out if AAV-mediated gene replacement combined with an enriched environment or a physical exercise program results in better treatment outcomes in a mouse model than gene replacement alone.

Meanwhile, Dr. Colleen Niswender’s lab at Vanderbilt is addressing the MECP2 dosing issue. Since a variety of MECP2 mutations can cause Rett syndrome, her lab is testing if the optimal dose of MECP2 depends on which mutation is present using a mouse model. The results of these investigations will critically inform the design of the safest and most beneficial gene replacement treatment for humans.


Gene activation uses existing good MECP2

Another way to treat Rett syndrome involves using the normal MECP2 gene that female cells already have. You may have heard that Rett syndrome is an X-linked disorder. This is because MECP2 is located on the X chromosome. Females have two X-chromosomes, whereas males have one X-chromosome and one Y-chromosome. Only one X-chromosome can be active in each cell. This means that in females with Rett syndrome, the cells in the body are mosaic: some have the working MECP2 gene turned on and some have the nonfunctional MECP2 gene turned on. The other X-chromosome is still in each cell, but it has been turned off.

Several of our researchers are working to get the good MECP2 gene females with Rett syndrome already have turned on again. Dr. Jeannie Lee’s lab at Massachusetts General Hospital is using a combination of drugs to turn on the entire otherwise inactive X-chromosome. Dr. Kyle Fink’s lab at UC Davis is taking advantage of recent breakthroughs in gene-editing technology, CRISPR, to turn on just the silent MECP2 gene. Meanwhile, Dr. Chrystal Zhao at Sanford Burnham Prebys Medical Discovery Institute will determine whether blocking a regulator of X-chromosome silencing results in reactivation. All three researchers are testing their approaches in mouse models and cell cultures derived from Rett syndrome patients to accelerate any successes to the clinic. Their important work will help identify the best methods for unlocking the potential of a female patient’s good MECP2.


RNA editing corrects the course of defective MECP2

While MECP2 mutations cause Rett syndrome, it is the protein product of the MECP2 gene (rather than the gene itself) that creates all the problems. The path to making this protein requires a MECP2 RNA intermediate, which offers the opportunity for another Rett syndrome intervention.

Dr. Thorsten Stafforst at the University of Tübingen, one of’s new awardees, is taking advantage of this opportunity. The goal of his research is to edit mutant MECP2 RNA so that it can make a normal protein. Cells already contain RNA editing machinery. Dr. Stafforst’s research aims to simply direct that machinery to mutant MECP2 RNA as a new and different way to treat Rett syndrome.

Hope for a better life on the horizon

It will take time to evaluate these different approaches. However, recent successes in gene modifying therapy research make us cautiously optimistic that a transformative treatment for Rett syndrome is on the horizon. To assist our loved ones as soon as possible, we at will continue seeking treatments to alleviate symptoms and improve quality of life while we wait for this research to help create a world without Rett syndrome.

“We continue to explore approaches to treat Rett syndrome by gene therapy, and that future is looking brighter. It was a fellowship from RSO in 2007 that started me working on gene therapy for Rett syndrome, for which I’ll always be thankful.”
~ Dr. Steven Gray