Gene Replacement

This is RSRT’s lead strategy and the one closest to clinical trial.

Rett Syndrome, as awful as the symptoms may be, provides us with several big advantages. First, we know the cause: mutations in a single gene, MECP2. Second, Rett is not degenerative – brain cells don’t die. All the different kinds of brain cells are present and all are in the correct places. Third, work from RSRT trustee Adrian Bird suggests that the symptoms of Rett need not be permanent. These three facts make gene replacement an exciting and promising therapeutic strategy.


What it is

The concept behind gene replacement is simple. Deliver healthy genes to compensate for mutated genes. Gene replacement is a one-and-done strategy.

Why it matters

We know that the many symptoms of Rett are caused by mutations in a single gene, MECP2, which in turn makes a mutated protein. Numerous experiments in mice have shown that restoring levels of the MECP2 protein reverses symptoms. While we don’t yet know how the animal results will translate to people there is the expectation that dramatic improvements are possible.


Research directly funded by RSRT has resulted in two gene replacement industry programs, AveXis/Novartis and Taysha Gene Therapies, and two academic programs, University of Pennsylvania.and University of Edinburgh.

Early Leaps, Promising Result

RSRT started funding gene replacement efforts in 2010, at a time when gene therapy for neurological disorders was still considered science fiction. Encouraging data led to the launch of the RSRT-funded Gene Therapy Consortium in 2014. The Consortium included gene therapists Brian Kaspar and Steve Gray, and MECP2 experts, Stuart Cobb and Gail Mandel.

The Consortium worked through challenges involving vector optimization (the Trojan horse that delivers the gene into a cell), gene construct optimization (what you package into the vector), dosage, and the routes of administration into the body.

The data generated by the Consortium exceeded our expectations. They developed a gene replacement product candidate with impressive efficacy, safety, and delivery characteristics. The magnitude of improvement seen in Rett mouse models treated with gene replacement is much greater than that of any drug tested to date and suggests that significant benefit may be achieved in people.

Importantly the Gene Therapy Consortium incubated two industry programs and two academic programs.

Improvement seen in Rett mouse models treated with gene replacement is much greater than that of any drug tested to date.


Based on the data generated by the Gene Therapy Consortium, the biotech company AveXis is advancing a gene replacement candidate, AVXS-201.

We expect an update from AveXis/Novartis later this year regarding when the clinical trial will begin. The trial will be the first opportunity to test a therapeutic that targets the root cause of the disease.

AveXis/Novartis has an approved gene therapy product on the market, Zolgensma, for a devastating neurodegenerative pediatric disease called spinal muscular atrophy Zolgensma is saving lives and allowing babies who could not even hold their head up to walk and talk.

Taysha Gene Therapies

Taysha Gene Therapies is a recently launched biopharma company that is pursuing MECP2 gene replacement based on research conducted by Steve Gray, a member of our Gene Therapy Consortium. The company plans to start a Rett clinical trial by the end of 2021.

University of Pennsylvania
Gene Therapy Program

The Gene Therapy Program, the largest academic gene therapy program in the world, is led by pioneer gene therapist James Wilson, MD, PhD. Dr. Wilson has played a pivotal role in the renaissance this field is currently experiencing. He’s made a number of seminal discoveries, including the identification and development of the AAV9 vector, the gold standard for delivery to the brain.

One of Dr. Wilson’s overarching objectives is improving delivery of genes to the brain which is of course extremely relevant to Rett Syndrome.

The goal is to have the product ready for clinical testing in 2022.

University of Edinburgh

Adrian Bird, PhD and Stuart Cobb, PhD, both at the University of Edinburgh, are collaborating closely to advance a gene replacement therapeutic into the clinic.

Adrian Bird is world’s leading expert on MECP2 and has become synonymous with Rett research. He discovered the MECP2 protein in the early 1990s; made the first mouse model that is used in hundreds of labs around the world; published the landmark paper that established the principle of reversibility for the disorder; and has made many significant contributions to the understanding of the function of the MECP2 protein. Adrian Bird is a founding trustee of RSRT.

Stuart Cobb is an original Gene Therapy Consortium member. His introduction to Rett came over 15 years ago when he was approached by Professor Bird to conduct some neurophysiology experiments. He was a co-author on the 2007 reversibility paper and published the first gene replacement study in male mice using AAV2 and AAV9 vectors. Besides traditional gene replacement strategies Dr. Cobb is also pursuing RNA modification approaches.

Drs. Bird and Cobb are working to:

  • More deeply understand the function of MECP2 to develop more effective gene therapy products
  • Design novel gene therapy cassettes to enable better regulatory control of the MECP2 protein
  • Design tunable systems that allow gene therapy to be turned off if necessary

A cure for Rett.
You want it.
We want it.

Great achievements happen when people stand up and say I’m in. I will be part of the solution!

Rett may be a rare disorder but together we are powerful.