At the Rett Syndrome Research Trust, we work to drive the development of cures for Rett Syndrome. From 2017 to 2020 during Roadmap to a Cure, we identified six therapeutic strategies for developing cures for Rett. We asked you, our Rett families, to support this research and to raise funds from your relatives, friends, and neighbors through events and crowdfunding. And you came through: the Rett community raised $33 million.
With your actions and support, we funded research in understanding the basic biology of Rett Syndrome, we created research tools that scientists can use to model Rett like animals and human cell lines generated with tissue collected from individuals with Rett, and we tested new therapies in these animals and cells. We incubated academic and industry research projects in six key strategic areas, giving scientists the financial support they need to develop the novel therapies.
And that research is paying off! Seven therapies using four different molecular strategies are being developed for clinical trials – all based on work or resources funded and generated by RSRT. These therapies address the root cause of Rett Syndrome: mutations in one copy of the MECP2 gene, which lead to a lack of MECP2 protein or a damaged MECP2 protein that the body can’t use.
The passionate support of Rett families around the world and the vision of RSRT has put Rett Syndrome squarely on the biopharma map. All of this has brought us to a critical juncture in Rett research in which we must expedite more biopharma companies picking up academic science and advancing it to clinical trials. It’s imperative that we keep our foot on the accelerator and leverage this momentum and excitement. We will continue to work tirelessly at RSRT to do this, and we hope all the families (and more!) that were behind us for Roadmap to a Cure will help us with this next phase of the research. Find out how to take action to cure Rett Syndrome here.
Read on to learn more about the programs RSRT incubated now being pursued in biopharma.
Gene replacement therapy
- Companies: Novartis, Taysha Gene Therapies
- Curative strategy: In gene replacement therapy, a healthy copy of a gene is added to cells. Novartis has a proven track record of success using gene replacement therapy to treat spinal muscular atrophy. Building on their knowledge from this success, scientists at Novartis plan to deliver a healthy copy of the MECP2 gene to cells in the spinal cord and brain. Cells will use this copy of the gene to make the fully functional MECP2 protein that individuals with Rett lack. Taysha Gene Therapies has created a similar treatment that uses a shortened version of MECP2 (a “minigene”) instead and includes an additional DNA sequence intended to regulate how much MECP2 each cell makes so it is in just the right range. Learn more about gene replacement therapy.
- Timeline: Both companies are applying to the FDA for approval for clinical trials by the end of 2021. Trials could start as soon as approval is granted.
- Benefits: Gene replacement therapies are the closest to the clinic, have a proven track record, and have potential to help patients with any mutation.
- Challenges: It’s not possible to control how many copies of MECP2 end up in cells. This could lead to too little or too much MECP2 protein in a given cell.
- RSRT’s role: Data generated through RSRT’s Gene Therapy Consortium and MECP2 Consortium formed the basis for Novartis and Taysha’s Rett programs.
- Companies: Beam Therapeutics
- Curative strategy: In gene editing, molecular tools are used to change the sequence of an individual's DNA, correcting disease-causing mutations. Beam Therapeutics is developing a treatment that uses base editing, a type of CRISPR gene editing, to correct certain mutations in the MECP2 gene that lead to Rett. Learn more about gene editing, and hear from scientists at Beam who are working on this treatment.
- Benefits: Gene editing could restore a healthy DNA sequence by permanently reversing the mutation in the cell’s existing MECP2 gene. This approach avoids issues around “dosage” of MECP2 protein because the normal methods that regulate how much MECP2 protein is made remain intact. Right now, base editing could be used to correct some common mutations, but not all of them. However, research in this field is progressing rapidly and our expectation is that more and more mutations will be amenable to editing in the future.
- Challenges: It may be tough to edit enough cells to have a meaningful effect. It’s also possible that the treatment could have off-target effects, meaning making permanent changes somewhere else in the DNA that may or may not be harmful. Scientists continue to make progress to improve specificity so off-target edits happen rarely or not at all.
- Timeline: Beam’s treatment is still in early stages, with clinical trials at least several years away.
- RSRT’s role: RSRT is fully funding Beam’s Rett therapy development.
- Companies: Alcyone Therapeutics, Herophilus
- Curative strategy: Each of our cells has two copies of each of our chromosomes, and therefore two copies of every gene. Girls with Rett Syndrome have one healthy copy of the MECP2 gene on one X chromosome, and a copy with a Rett Syndrome mutation on the other. Cells with two X chromosomes will randomly inactivate one of them so only one X chromosome is used, and therefore only one copy of MECP2 makes protein. Some cells use the X chromosome with the healthy copy and some cells use the X chromosome with the Rett mutation. In MECP2 reactivation, the goal is to activate the healthy copy of MECP2 on the inactive X chromosome to rescue the cells making MECP2 with the mutation. Learn more about MECP2 reactivation. Alcyone is working with researchers at the University of Virginia to create an approach that reactivates the inactive X chromosome, including MECP2. Herophilus is using a unique research approach that includes brain organoids – patient cells grown in a lab that form three-dimensional shapes, like a tiny organ – to develop their treatment. They are aiming to reactivate just the healthy copy of MECP2 in cells where it is inactive.
- Benefits: This treatment approach has the potential to restore healthy MECP2 protein to girls and women with any MECP2 mutation, without the potential risks that come with altering DNA sequence or adding new DNA to a cell. This strategy is the only strategy that RSRT is pursuing that could not be used for boys with Rett Syndrome since boys don’t have an inactive X.
- Challenges: If Alcyone’s treatment is effective, there may be side effects from reactivating other genes on the X chromosome. For Herophilus, the challenge will be getting enough cells to reactivate the healthy copy of the gene.
- Timeline: Clinical trials are likely to begin in two to three years, starting with the Herophilus treatment.
- RSRT’s role: Before they were lead advisors at Alcyone, Sanchita Bhatnagar and Katherine Meyer both did research on Rett Syndrome in labs supported by RSRT. Furthermore, RSRT introduced these scientists, creating a crucial collaboration for Alcyone’s treatment. RSRT provided Herophilus with Rett patient cell samples from our biorepository, which they use to make organoids and model disease and treatment.
- Companies: Vico Therapeutics, Shape Therapeutics
- Curative strategy: Our genes hold the master copy for instructions for making all the proteins in our bodies, written in the language of DNA. DNA is kept safe inside a special compartment of a cell called the nucleus. To make a particular protein, a disposable copy of genetic instructions is made in messenger RNA (mRNA). The mRNA molecule travels out of the nucleus where it works together with other cellular machinery and transfer RNAs (tRNAS) to make protein. In Rett Syndrome, mutations in the MECP2 gene lead to mRNA that codes for a protein that doesn’t work because it has an incorrect building block, or a stop signal in the middle of the protein, leading to a shortened, non-functional version of the protein. Because mRNA sometimes naturally has mistakes in it, cells have ways to edit mRNA. Researchers at Vico are taking advantage of proteins that cells normally use to edit mRNA, engineering them to correct Rett mutations in mRNA, or skip over signals in the mRNA that shorten the MECP2 protein. Researchers at Shape are engineering a special kind of tRNA that skips over stop signals in the wrong place. Learn more about RNA editing in this overview, and go in depth on the two approaches with RSRT webinars with scientists at Vico and Shape.
- Benefits: These approaches are being used to treat individuals with specific mutations, including R168X , R255X, R270X, and R306H, which together account for about 40% of disease-causing mutations. RNA editing approaches could help restore MECP2 protein without the potential risk that comes with altering the DNA sequence, adding new DNA to a cell or activating other genes on the X chromosome.
- Challenges: So far, RNA editing can be used to address some mutations, but not all of them. There is the potential for off-target effects, meaning, RNA for other genes might sometimes be accidentally edited, too.
- Timeline: Clinical trials are likely to begin within three years.
- RSRT’s role: RSRT has funded Gail Mandel, co-founder of Vico, for over a decade. With our support, Dr. Mandel created the Rett model mouse that has been crucial in her continued work, as well as other Rett research. RSRT provided Shape Rett patient cell samples from our biorepository, which they use to model disease and treatment.
We don’t know yet which strategies will be most effective for addressing Rett Syndrome, but with so many clinical trials on the horizon, families of Rett individuals have reason to be optimistic. And in addition to the treatments described above, your generous contributions will continue to fund additional academic programs that we expect will transition to biopharma during the next few years.
With the exception of the Herophilus MECP2 reactivation program which will be a small molecule drug, the rest of the programs will require a delivery vehicle to get these biologic therapeutics into cells. The current gold standard for delivering biologics to the brain is a vector called adeno-associated virus 9 (AAV9). There is an aggressive global effort to discover other viral vectors that can distribute diffusely throughout the brain better than AAV9. A new generation vector when identified could be used for these programs. Furthermore, research into delivery methods that use non-viral technologies is also very active. Delivery methods like the lipid nanoparticles used in the COVID-19 mRNA vaccines are being developed for delivering biologic therapeutics. RSRT is actively monitoring progress in the delivery space.
“I’ve been working with the scientific and clinical community for 22 years,” says RSRT Founder & CEO Monica Coenraads. “For years I’ve yearned to see Rett Syndrome on biopharma therapeutic pipelines. That time has now come. And it’s a direct result of the fundraising efforts of Rett families and RSRT’s laser focus on a cure. Until there is a cure our work is not yet done. You can count on RSRT continuing our track record of investing in the right people and the right projects. And we in turn count on the continued fundraising effort of families.”