Genetic solutions for a genetic disorder
What causes Rett syndrome and the importance of targeting the root cause
Rett syndrome is caused by alterations in a single gene called MECP2. In 2007, one of the members of our board of trustees, Sir Professor Adrian Bird, made a landmark discovery: that the symptoms of Rett were reversed in mice when levels of the MECP2 protein – the protein created by the MECP2 gene – were restored to normal. Subsequent MECP2 gene replacement studies resulted in symptom improvement much greater than that of any drug or compound tested to date. For this reason, and because Rett is a single-gene disorder with no evidence of brain cell death, we are completely focused on delivering a cure by targeting MECP2 itself.
Our CURE 360 plan attacks the root cause of the disease from every angle. We have no doubt the cure will come from one of these six priority research strategies.
Gene replacement therapy introduces healthy copies of the MECP2 gene into the body to compensate for the mutated one. This is the strategy that is closest to the clinic. RSRT-funded research has advanced multiple gene replacement programs for Rett.
Gene editing fixes the underlying mistake in the MECP2 gene using a technology that has taken the scientific world by storm: CRISPR. RSRT supports two efforts in the gene editing space.
MECP2 Gene Reactivation
The MECP2 gene is on the X chromosome, and all females have two X’s. Beside each active, mutated gene rests a healthy but silent twin. Reactivation could mitigate the flawed gene by reawakening its silenced counterpart. RSRT has championed research in this area since our launch in 2008.
RNA is a copy of DNA, and therefore any mutations found in a gene are also found in its RNA. We are advancing a number of RNA editing efforts, all of which harness normal editing processes that already exist in our cells. RNA is a copy of DNA, and therefore any mutations found in a gene are also found in its RNA. We are advancing a number of RNA editing efforts, all of which harness normal editing processes that already exist in our cells.
RNA trans-splicing harnesses a naturally occurring biological process to splice or cut out the section of MECP2 RNA where almost all the mutations are and insert a healthy replacement.
Rather than target the gene or the RNA, this strategy delivers the end product, the MECP2 protein.
MECP2 Therapeutic Pipeline
Because of RSRT's efforts there is an extensive pipeline of programs that target MECP2, the gene responsible for Rett when mutated, at biopharmaceutical companies and in academia.
- Research & DiscoveryThe earliest stage of development encompassing basic research to identify therapeutics.
- Proof of ConceptPreliminary experiments, typically performed in test tubes, cells or mice, that confirm the expected beneficial therapeutic effects.
- Safety & ManufacturingRequired studies that assess safety, tolerability, efficacy and dose ranges prior to initiating human studies.
- Clinical TrialsTesting of the therapeutic in humans, first for safety and then for efficacy. This may be done in a series of trials with a single objective, or in single trials with multiple objectives.
- Available TherapeuticTherapeutic has demonstrated safety and efficacy and can be commercialized by companies and used by doctors to treat patients outside of a clinical trial.