Gene Replacement

Gene replacement is RSRT’s lead strategy and closest to clinical trial.

What it is

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

Why it's part of our plan

Many Rett symptoms 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. Gene replacement will add more healthy MECP2 genes to the brain, leading to more healthy MECP2 protein. Although we don’t yet know how the animal results will translate to people, there is the expectation that dramatic improvements are possible. Gene replacement is applicable for all MECP2 mutations.

Challenges

Delivery of gene therapy to as many brain cells as possible is a crucial objective. But the current gold standard for therapeutic delivery to the brain, the AAV9 vector, has a number of limitations.

Status

Research directly funded by RSRT has resulted in two gene replacement industry programs that are now in the clinic, Taysha Gene Therapies and Neurogene.

RSRT-Led Gene Therapy Consortium

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. 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 an academic program.

Gene Replacement Programs

RSRT has invested more than $10 million in gene replacement. RSRT-driven collaborations, initiatives, and investments have helped to generate all of the following gene therapy programs.

Taysha Gene Therapies

Taysha Gene Therapies is pursuing a MECP2 gene replacement program, called TSHA-102. This gene replacement program is designed to deliver a shortened version of the MECP2 gene (mini-gene) as well as a novel platform technology called miRARE, which should control the level of MECP2 expression. The mini-gene was developed by Sir Professor Adrian Bird and funded by RSRT as part of the MECP2 Consortium. The miRARE platform was developed by Dr. Steve Gray and funded by RSRT as part of our Gene Therapy Consortium. Taysha's trial has startedin Canada for individuals with Rett 18 years and older. Preliminary results on patient #1 have been reported.

Taysha Doses Patient #2 - September 26, 2023
Taysha Reports on Patient #1 - August 14, 2023
Taysha Cleared to Dose Second Patient - July 31, 2023
Taysha Doses First Rett Syndrome Patient - June 5, 2023
Taysha Provides Update for their Rett Gene Replacement Program - February 1, 2023
Taysha Rett Community Letter Announes First Clinical Trial – March 30, 2022
Taysha Announces Age Range of First Trial - September 23, 2021
Taysha Rett Community Letter – February 17, 2021
Taysha Rett Community Letter – October 14, 2020

Neurogene

Neurogene was launched in 2018 and in 2022 announced the addition of a Rett syndrome gene replacement program, NGN-401, to their company pipeline. NGN-401 delivers a full-length MECP2 gene with a novel technology, called EXACT, that allows the amount of protein made by the gene to be regulated in order to avoid high levels. NGN-401 is administered via injection into the ventricles of the brain. This type of injection is called ICV (short for intracerebroventricular).

This gene replacement program was developed by Dr. Stuart Cobb with almost $3 million of funding from RSRT. Dr. Cobb was part of our Gene Therapy Consortium, which launched in 2014.

The trial is recruiting girls with Rett between the ages of 5 and 10.

Joseph Anderson

At the end of 2021, RSRT approved funding to Joseph Anderson, PhD, of the University of California, Davis, for a novel approach to treating Rett. The approach involves extracting a particular type of cells found in blood and bone marrow called hematopoietic stem cells. The stem cells are then filled with MECP2 genes, encapsulated in a lentivirus, and reintroduced into the body through an intravenous infusion. Some of the stem cells will find their way to the brain, where they will act as factories that continuously supply the MECP2 protein.

This approach, championed by Anderson, has had success in Angelman syndrome animal models, and a clinical trial for Angelman syndrome is now being planned. Should this approach turn out to be feasible for Rett, it would open the door to a novel approach that eliminates some of the issues encountered with AAV therapies.

Gene Editing

Gene Replacement