Clinical Resources

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.

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:

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

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, non-profit 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.

Improving subjective surveys and objective wearable technology will expedite therapy development.

Wearables and other promising technologies

Another avenue is to develop objective measures that can be assessed at home over extended periods of time, which 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 Gari Clifford, PhD, of Emory University and Georgia Institute of Technology, and 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.

Biomarkers

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.

Our goal is to identify biofluid biomarkers as a tool to document efficacy, guide dose selection, and improve safety for Rett patients receiving treatments.

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.

Biorepository

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, 8 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.

To inquire about our cell lines, please email Monica Coenraads.

Registry

We are excited to be working with DSG Inc., a leader in clinical data services and a global partner in biopharm 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 registry is currently being built. The projected launch date is first quarter 2021.

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A cure for Rett.
You want it.
We want it.

Great achievements happen when people stand up and say I’m in. I will be part of the solution!

Rett may be a rare disorder but together we are powerful.