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Clinical Initiatives

Individuals with Rett front and center

From improved trial endpoints to a registry and biorepository, knowledge about individuals with Rett drives the drug development engine.

All of the Cure 360 strategies will need to be tested in clinical trial settings. The resources below are aimed at improving clinical trial design to ensure they are conducted efficiently and effectively.

Rett Syndrome Global Registry

We are excited to be working with DSG, Inc., a leader in clinical data services and a global partner in biopharmaceutical clinical trials to develop a unique registry for individuals with Rett syndrome.

Registries often collect contact information for patients with a particular disorder and provide basic summary data about mutations, symptoms, and disease progression with the goal to educate the medical community and support therapeutics development. Aside from these very important registry functions, our registry will provide unique opportunities for parents, such as a personal dashboard to show how your child compares to others; a way to log and track symptoms and medications over time; and provide a centrally accessible, private location to store your records and data of interest for yourself or for physicians.

We will also have the ability to conduct citizen research within the registry to test wearable and non-wearable devices in the real world, validate new or revised questionnaires, and conduct remote clinical studies.

Our platform is designed to be versatile so that we can change and grow with the community as our needs change. Our hope is that the registry will revolutionize the way we treat Rett. All you’ll need to access this centralized wealth of information incorporating the latest advances in real-world data capture will be an internet connection on your computer or mobile device.

The Global Registry is currently being built. The projected launch date is early 2022. View the study listing on

Cure Rett Working Group

The Cure Rett Working Group is indicative of RSRT’s innovation to bring scientists together to tackle the biggest challenges to curing Rett. Throughout 2021 the Cure Rett Working Group, gathered together leading scientists and subject matter experts with the goal of developing a roadmap for accelerating promising therapeutic candidates into clinical trials. Discussions covered topics such as the biology of the MECP2 protein, DNA and RNA editing, delivery of therapeutics to the brain, and symptom assessment and biomarkers. The roadmap, once published, will be a critical tool in paving the way for clinical trials no matter what the therapeutic approach.


A critical resource for conducting research is patient-derived cells. As part of our initiative to develop a repository of cellular tools to aid Rett research, we have collected skin and blood cells from individuals with Rett syndrome. More than 30 families representing 18 different mutations have generously donated their child’s cells for future research and the creation of induced pluripotent stem cells (iPSCs).

iPSCs are a highly desirable cell type because their cell identity has been erased, and they have the capacity to become any type of cell if given the right nutrients and growth signals. iPSCs are critical for Rett because these cells can become neurons or other types of brain cells, providing a human model for testing of potential therapeutics. Though animal models of Rett are extremely valuable for early stage research, biologic therapeutics must ultimately be optimized for human DNA or RNA sequences. Specifically, the genetic sequence of the MECP2 gene is similar, but not identical, to the gene in mice, rats, or even nonhuman primates. RSRT’s human cell repository allows the sharing of these human cell resources with academia and biopharma alike, to facilitate new discoveries and advance translational therapies into the clinic.

To date, eight companies developing potentially curative Rett therapeutics have requested cells to further their development efforts. To ensure these precious resources are used to further Rett research, all requests and research proposals are approved by RSRT.

Outcome Measures

Our goal is to develop devices and data analytics that can assess Rett-specific symptoms such as altered breathing, oxygen saturation, heart rate variability, and other difficult-to-measure but clinically meaningful symptoms in Rett patients. Doing so will directly support therapeutic development of a curative therapy. Once these devices or analytical methods are optimized to assess physiological Rett symptoms, they could also be used as biomarkers to gain insight into the effects of MECP2-corrective strategies earlier in treatment than those symptoms that require skill development or learning.

More accurate assessment

Critical to conducting efficient and effective clinical trials is the ability to assess symptoms, function, or health of a patient before, during, and after treatment. These assessments are called outcome measures and can include questionnaires that clinicians or parents complete, or functional tests that directly assess specific skills and abilities. Treatment-induced improvements in outcome measures compared to non-treated individuals that are both statistically sound and clinically meaningful are required for therapeutics to be approved by FDA and other regulators.

In Rett syndrome, clinician- and parent-rated questionnaires are used to assess the effect of a therapeutic, and functional tests focused on specific skills or tasks are being explored. Questionnaires, though standard in most neurological disorders, are dependent on someone observing or interpreting the patient’s symptoms and can suffer from a lack of reproducibility for various reasons. The most commonly used questionnaires require that caregivers make subjective assessments and are typically not sufficiently sensitive to pick up minor improvements.

Partnership with RTI International

We have efforts underway to determine if the questionnaires currently in use adequately assess parent concerns and Rett symptoms or if they could be improved to address the current challenges. Alternatively, an entirely new questionnaire may be needed.

In our initial review of current parent-rated questionnaires we have partnered with RTI International, a world-renowned nonprofit research institute with broad experience in developing and evaluating questionnaires, among other specialty services. In collaboration with leading Rett clinicians, we are working to improve the way parents and clinicians assess the symptoms of Rett syndrome to provide better tools to assess therapeutics.

Together, these efforts to improve subjective questionnaires and create objective wearable and non-wearable technologies will facilitate and expedite drug development.

Observer-Reported Communication Ability (ORCA)

Most parents of non-verbal children would agree that communication is at the top of the symptoms list they would like addressed. Currently a communication-focused assessment tool does not exist for Rett. However, one does exist for Angelman syndrome (a disorder with similarities to Rett), called the Observer-Reported Communication Ability (ORCA). We are leveraging the efforts already invested in ORCA by the Angelman community to adapt ORCA for Rett.

The ORCA was developed by the Center for Health Measurement (CHM) at Duke University School of Medicine. It includes 72 questions that capture various types of expressive, receptive, and pragmatic forms of communication and places individuals on a continuum of communication ability that detects changes over time. The ORCA does not rely on speech, but allows gestures, vocalizations, and use of aids to capture communication ability. It takes about 15-20 minutes for a parent/caregiver to complete the measure independently, and it does not require the help of a clinician or speech language pathologist. The ORCA is now being used in clinical trials and natural history studies for individuals with Angelman syndrome.

RSRT has provided funding to Dr. Reeve, the director of CHM, and his team to develop the ORCA for Rett. Through one-on-one interviews with parents of individuals with Rett, the measurement tool will be adapted for use in Rett syndrome, and then work can begin to validate the new assessment. Our hope is that the ORCA will become the standard tool to assess communication abilities in Rett syndrome and an important addition to assessing efficacy in therapeutic development.

The ORCA study aimes to enroll 270 Rett syndrome families from English-speaking countries, including the US, Canda, United Kingdom, and Australia. Families that are interested in learning more about the ORCA study for Rett syndrome are encouraged to complete the form below.

ORCA Study

Wearables and other promising technologies

Wearables and other promising technologies

Another avenue is to develop objective measures that can be assessed at home over extended periods of time, measures that do not require caregiver observation or interpretation. To meet this need, we’re evaluating and developing wearable and non-wearable devices that can directly measure physiological symptoms and function in Rett individuals. We are focused on the most promising technologies to assess feasibility and utility for families to use in their homes. Key criteria will be ease of use, capability to detect important symptoms and functional abilities, and open access to data.

A few leaders in the space of wearable and non-wearable devices we are currently evaluating include MC10, Inc (nPoint), Carre Technologies (hexoskin), and Emerald Innovations (Emerald), and we are always on the lookout for new technologies and devices. We have partnered with Dr. Gari Clifford, PhD, of Emory University and Georgia Institute of Technology, a leader in the field of data analytics and artificial intelligence, and Vivosense, Inc., a data analytics group with an innovative platform, to identify Rett-specific patterns in the physiological data collected by these devices.

We are evaluating these devices from data captured in a small academic pilot study and have now expanded our development of the most promising devices. In an ongoing FDA-regulated study assessing oral ketamine in Rett patients, we are assessing whether the beneficial effects observed in mouse models of Rett will also be observed in humans. Specifically, we are assessing the effect of ketamine in humans on the same physiological symptoms that were improved with ketamine administration in the mouse models. A second study will evaluate next-generation devices with new capabilities.


A biomarker is a defined characteristic that can be measured as an indicator of a disease state. Examples of biomarkers include cholesterol for heart health and blood pressure for stroke risk.

Biomarkers are important in developing therapies because they help researchers understand whether or not a therapy is working, guide dose selection, select the most suitable individuals for a treatment or study, and assess safety.

In the absence of such a biomarker our current assessment of therapeutics is restricted to the measurement of symptoms and/or improvement in function. Both could take a relatively long time to improve. It would be a huge advantage to know early on if treatments are working by detecting changes in cellular read-outs caused by MECP2 correction rather than waiting to see if symptoms improve.

Treatments that affect MECP2 expression in the brain are likely to be difficult to measure short of taking a brain biopsy, which is obviously not a desirable option. Our current efforts are focused on identifying a cellular read-out in a biofluid such as saliva, blood, urine, or spinal fluid.

Victor Faundez, PhD

Dr. Victor Faundez, PhD, of Emory University, is taking a unique and comprehensive approach to identify biofluid biomarkers. By analyzing Rett mouse and rat models, along with human neuronal cell culture and Rett patient spinal fluid, Dr. Faundez has identified a set of overlapping cellular read-outs that correlate across Rett disease models and patients. These biomarker data, when combined and confirmed in more than one model system, strengthen the likelihood that a human read-out will be accurate and sensitive to changes in MECP2.

Recognizing the importance of biomarkers, we are building a consortium of investigators to work collaboratively to identify and validate.

Clinical Trial Consortium

RSRT has partnered with leading Rett clinicians to create a core clinical team poised to develop and conduct clinical trials and innovative studies. The Clinical Trial Consortium members are currently participating in the ketamine study and biosensor/device development studies.

Our Clinical Trial Consortium consists of the following investigators and associated Rett centers:

Dr. David Lieberman, MD, PhD; Boston Children’s Hospital
Dr. Eric Marsh, MD, PhD; Children’s Hospital of Philadelphia
Dr. Jeffrey Neul, MD, PhD; Vanderbilt University
Dr. Alan Percy, MD; University of Alabama at Birmingham