The first in-human gene replacement trial is a major milestone for any genetic disorder. For our community it’s a moment that was a long time in the making and not without its disappointments — specifically, the Novartis termination of their Rett program last fall. So it is wonderful to see a gene replacement program progressing to clinical trials.
Without RSRT this program is unlikely to have advanced. The genetic cargo being delivered is composed of two key elements: a mini-MECP2 gene that was generated by Adrian Bird, PhD, with funding from RSRT, and a feedback mechanism that allows for regulation of the amount of MECP2 protein being produced. This mechanism was developed by Steve Gray, PhD, with funding from RSRT as part of our Gene Therapy Consortium. Finally, the mini-gene intellectual property (IP) that was licensed by Taysha was filed by the University of Edinburgh at the strong encouragement of an RSRT advisor. Without the IP there would be no business model for Taysha to pursue.
Of course, our goal is not to get to a trial. Our goal is to have a therapeutic that dramatically improves our loved one’s symptoms. So, while we celebrate this milestone, we await the results of the trial with cautious optimism.
Neurogene Adds Rett Program
In May Neurogene announced that they are pursuing a gene replacement program for Rett. The program is the result of many years of research in the lab of Stuart Cobb at the University of Edinburgh. He was also a member of our Gene Therapy Consortium and an RSRT funded scientist for the last decade. I am a great admirer of Stuart’s research and after introducing him to Neurogene in 2018 was delighted when he became Chief Scientific Officer and able to focus the full resources of the company on accelerating the development of the Rett gene therapy program. I look forward to updates from Neurogene as their program advances towards the clinic.
Rett Symptoms in Mice Alleviated with RNA Editing
RNA editing has generated a great deal of excitement in the last handful of years. Gail Mandel, PhD, and her extremely talented post-doctoral fellow John Sinnamon, PhD, have been smack in the middle of this excitement having authored a trio of papers on RNA editing for Rett. The latest paper published this summer is a pivotal one, as it is the first to show symptom alleviation in a mouse model of human disease. Potentially 45% of Rett syndrome mutations are repairable by RNA editing, including the common nonsense mutations. Future studies will focus on improving the efficiency of editing and symptom rescue in models of these mutations. RSRT has funded the Mandel lab for over a decade. This funding, which accelerated the lab’s RNA editing progress, has incentivized Vico Therapeutics, Shape Therapeutics, and Wave Life Sciences to pursue RNA editing programs for Rett syndrome.
RSRT Launches Outcome Measure and Biomarker Consortium
To date, Rett syndrome clinical trials have relied on questionnaires like the Rett Syndrome Behavioral Questionnaire (RSBQ) and the Clinical Global Impression of Improvement (GGI-I) to determine if treatments being tested were working. These questionnaires are dependent on parents or physicians observing and interpreting patients’ symptoms, which are relatively subjective and potentially biased. Our goal is to move away from questionnaires when possible and collect objective data directly from the patient.
RSRT has been testing biosensors that measure breathing, sleep, seizures, and heart rate variability directly from the patients. We are now embarking on measuring movement such as gait, tremors, and hand function. We are also analyzing EEGs. This year we launched an outcome measure and biomarker consortium with participants from every biopharmaceutical company with a genetic-based Rett program. Together with biosensor and medical device companies, physicians, data analysts, and academics, RSRT is developing a validation plan for objective outcome measures and biomarkers to submit to the FDA. I firmly believe that having reliable and objective assessment tools and/or biomarkers will open the floodgates to even more biopharma interest.
Molecular Biomarkers Identified for Rett Syndrome
The lab of Victor Faundez, PhD, which is pursuing molecular biomarkers that track with MECP2 status, published important findings from work we funded as part of our Roadmap to a Cure campaign. They identified two key proteins measurable across multiple species, including humans, that should give clues about how much MECP2 is restored in curative therapeutic trials. It is possible to measure these proteins in cerebrospinal fluid, and both Taysha and Neurogene are planning to look for these proteins in their clinical trials.
Until this discovery, molecular biomarkers that track with MECP2 status or disease severity have eluded the field. But Victor’s unique approach to look across different species and evaluate tissues and fluids separately has uncovered critical relationships that led to the identification of these biomarkers. This is important because it means that changes in these proteins in cerebrospinal fluid have potential to be the first indication of how well a genetic drug is working and could inform if dosing is high enough, if enough cells are corrected, and ultimately predict whether improvement in symptoms, which may take time, can be expected.
Digital Natural History Study
It makes total sense that before you cure a disease you need to understand it. Traditionally that understanding has come from in-person clinic visits where expert doctors gather information about patients and how their symptoms change over many years, collectively adding to the knowledge base of the disease. This type of effort is called a natural history study.
Because of technological advances, we now have an incredible opportunity to conduct digital natural history studies much faster by tapping into electronic medical health records. By gathering and consolidating years of existing medical records in one fell swoop we can create a comprehensive and accurate dataset to complement and enhance the existing natural history study for Rett syndrome. This approach provides detail on every medical visit, hospitalization, lab work, imaging, and prescribed medications without relying on caregivers’ memory or doctors asking the right questions.
Last year we initiated a pilot digital natural history study with technology company Ciitizen to gather and digitize medical records from an initial cohort of people with Rett syndrome. We now have a dataset of 120 individuals with Rett that we are analyzing, and we look forward to sharing the data with the community in the near future. We are eager to continue recruiting for this study, since the more records we gather the more accurate the Rett digital natural history study will be.
Communication Assessment Tool Created for Rett
The Rett community unanimously agrees that improving the ability to communicate would greatly improve function and quality of life for our loved ones. In order to accurately evaluate therapeutic interventions, however, we first need an outcome assessment that sensitively measures clinically meaningful improvements in communication abilities that are specific to Rett. We learned of a communication tool, the Observer-Reported Communication Ability (ORCA), that had been developed by the Center for Health Measurement (CHM) at Duke University School of Medicine for Angelman syndrome. We then funded a study with the same team to adapt the ORCA for use in Rett.
This year, with the help of 300 Rett parents who enthusiastically answered the call to participate in this study, the data was collected and analyzed, and a publication has been submitted. We will continue to update the Rett community about ORCA progress and are happy to have this communication assessment tool now available for use in clinical trials.
Biorepository of Rett Cell Lines Is in Demand
As part of our Roadmap to a Cure campaign, RSRT established a collection of Rett patient-derived cell lines thanks to more than 30 families who generously donated their child’s cells, representing 18 different mutations. Demand for these cell lines have exceeded our expectations: To date, 41 biopharmaceutical companies and universities around the world are now in possession of the cell lines, conducting important new research, with an additional 10 in the pipeline to receive the cell lines soon.
The Rett Community Drives Research Forward
I am deeply conscious of the fact that all that I describe here would not be possible without the Rett families that fundraise for us, and their networks of relatives, friends, and colleagues who support us. I can’t thank you enough for the actions you take as Rett families and for your generosity as donors. Our chief development officer recently reflected on how Rett families and donors drive research forward. At RSRT we place great emphasis on transparency, and we feel profound gratitude to our entire community. We truly do need each other. We simply could not do our important work without you.
This past year has been remarkably busy and productive. My focus and that of my colleagues is fixated squarely on the year to come. We have a lot to accomplish. With you by our side all things are possible.
I wish you and your families a wonderful holiday season and a healthy, happy, and successful 2023.