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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 Sir Professor Adrian Bird, PhD, suggests that the symptoms of Rett need not be permanent. These three facts make gene replacement an exciting and promising therapeutic strategy.

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 Dr. Brian Kaspar, PhD, and Dr. Steve Gray, PhD, and MECP2 experts Dr. Stuart Cobb, PhD, and Dr. Gail Mandel, PhD.

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.



Based on the data generated by the Gene Therapy Consortium, the pharmaceutical company Novartis is advancing a gene replacement candidate, OAV-201, for Rett syndrome.

The company released a community statement in February 2021 with an updated timeline. The trial will be the first opportunity to test a therapeutic that targets the root cause of the disease.

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 a MECP2 gene replacement program, called TSHA-102, based on RSRT-funded research conducted by Dr. Steve Gray, a member of RSRT's Gene Therapy Consortium, and Professor Adrian Bird as part of the MECP2 Consortium. TSHA-102 is designed to deliver a shortened version of the MECP2 gene as well as a novel platform technology called miRARE, which should control the level of MECP2 expression. Taysha plans to file an Investigational New Drug (IND) application for TSHA-102 with the FDA by the end of 2021. Community updates from Taysha are available below.

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 Dr. James Wilson, MD, PhD. Dr. Wilson has played a pivotal role in the renaissance that 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 to improve delivery of genes to the brain, which is extremely relevant to Rett syndrome.

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

University of Edinburgh

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

Professor Bird is the 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, which is now 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. Professor Bird is a founding trustee of RSRT.

Dr. 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