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Clinical Initiatives

Individuals with Rett syndrome 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.

Community-Driven Initiatives

Rett Syndrome Global Registry

We are building the Rett Syndrome Global Registry with the hope that it will revolutionize the way we treat Rett syndrome. Registries typically collect contact information for patients with a particular disorder and provide basic summary data about symptoms, disease progression, and genetic mutations with the goal to educate the medical community and support treatment development. Aside from these very important registry functions, our registry will provide opportunities for parents and caregivers to centralize the information they collect about their loved one’s symptoms and care, track symptoms and skills over time, share data with clinicians to improve care and outcomes, connect with others in the Rett community and participate in Rett research.

We will also have the ability to conduct a variety of research studies within the registry, such as testing wearable and non-wearable devices in the real world, validating new or revised questionnaires, and conducting remote clinical studies.

The power of the Rett Syndrome Global Registry comes from the quality and volume of the information that Rett families share. Working with DSG, Inc., a leader in clinical data services and a global partner in biopharmaceutical clinical trials, we’ve designed a HIPAA-compliant, high-quality database. With aggregated, anonymized data from across the global Rett community, biopharmaceutical companies will be able to design more efficient drug studies and get effective drugs to market sooner.

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

Digital natural history study

We are partnering with Ciitizen, a company that collects, summarizes, and shares medical records digitally, to create a digital natural history study for Rett syndrome. A natural history study follows a group of people over time to help us understand how a disease develops and how it can be treated. Natural history studies are particularly important for rare disease drug development because they help to define what is measured in clinical trials. The data from a high-quality natural history study can be used as an “external control” group that is compared to the group of people receiving the test treatment. Having an external control group for Rett clinical trials is critical to make progress toward a cure, which is one of the reasons that RSRT is partnering with Ciitizen.

Typically, natural history studies require at least 10 years of data-gathering to produce meaningful information. The innovation of the Ciitizen natural history study is that we don’t have to start from year one. Instead, by gathering years of existing medical record data and consolidating it into one place, Ciitizen is piecing together the natural history of Rett in one fell swoop — and creating a more comprehensive and accurate dataset than we could have ever achieved with annual, in-person visits with Rett clinicians.

RSRT is currently funding a pilot study with Ciitizen to gather and analyze data from a cohort of people with Rett syndrome.

RSRT-Led Collaborations

Bringing top scientists together

At RSRT we identify and convene scientists from multiple disciplines so that they can collaborate on the common goal of a cure for Rett. This may sound like an obvious approach, but unfortunately most scientists are incentivized to work alone, competing with each other and diluting resources. At RSRT we foster collaboration because we know that scientific knowledge is dependent on every incremental discovery. Bringing together leading scientists in consortia and working groups has led to some of the biggest discoveries on the path to a cure for Rett.

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.

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 a 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

Biorepository

Cell lines, which refer to samples of living tissue, are particularly important for determining the potential of a treatment. When the ability to test in a human cell line is available, companies can study that treatment with more confidence and are more likely to do the additional work needed to get a drug from the lab into the clinic. To support this important need and get more treatments into development faster, RSRT established a collection of Rett patient-derived cell lines, also known as a biorepository, with the help of families who donated blood and skin samples from their loved ones with Rett. 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, 40 unique requests from around the world have been made to obtain these important resources. To ensure these precious resources are used to further Rett research, all requests and research proposals are approved by RSRT.

To access samples from the RSRT Biorepository (including fibroblasts and iPSCs), please email email Jana von Hehn.

You may review the RSRT iPSC collection at the Coriell Institute here and search the Coriell Institute’s resources for Rett syndrome here.

Outcome Measures

Before a treatment for Rett can become available for our loved ones, we must prove that the treatment works – and we know a drug works only when it meets objective measurements of efficacy. There are several types of objective measurements, or outcome measures, that can be used to determine a drug’s efficacy, typically related to how a person feels or functions, or their quality of life. No matter what the outcome being measured, the measurement must be objective, replicable, and sensitive enough to detect small changes.

Outcome measures are critical to conducting efficient and effective clinical trials because they assess the symptoms, function, or health of a patient before, during, and after treatment. 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 the FDA and other regulators.

To date we don’t have direct and objective measures that correlate with disorder severity for Rett syndrome. The lack of objective and standardized outcome measures for Rett hinders biopharma involvement in our disorder. Developing drugs is risky business, and companies are even further deterred when there are extra complications such as subjective, and therefore potentially ineffective or irreproducible, outcome measures.

At RSRT we have therefore made it one of our key objectives to develop more effective ways to measure Rett therapeutics in the clinic. Our goal is to develop a variety of assessments that can be used as outcome measures – including observer-reported assessments, biosensor devices, and data analytics – that can assess Rett-specific symptoms such as communication skills, 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.

Observer questionnaires

One set of outcome measures in Rett syndrome, like many other neurological disorders, relies on the interpretation of symptoms by others – typically parents and clinicians, through questionnaires and interviews.

Questionnaires, though standard in most neurological disorders, are dependent on someone observing or interpreting the patient’s symptoms – they typically require that caregivers make subjective assessments. The most commonly used questionnaires suffer from a lack of reproducibility for various reasons and are typically not sufficiently sensitive to pick up minor improvements.

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 current challenges. Alternatively, an entirely new questionnaire may be needed to meet the rigorous standards of clinical trials.

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. 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.

Communication assessment

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. Phase 2 of the ORCA study is currently enrolling 250 Rett syndrome families from English-speaking countries. Select “Learn More” to participate.

Direct outcome measures

Measurements from biosensors

Our biosensor initiative aims to develop direct and objective measures of Rett symptoms by testing wearable and non-wearable biosensors. These devices can directly measure physiological symptoms and function directly in people with Rett. Importantly, direct measurements don’t rely on parent or clinician interpretation and 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.

We have piloted a number of wearable biosensor devices that can measure things such as heart rate variability, breathing, sleep quality, body position, gait, and others, just by being worn on the body. Wearable biosensor devices collect direct and repeated measurements in an individual, and can provide significantly more accurate data over almost any period of time than standard symptom assessments. We are also working with the next generation of biosensors called invisibles, which are not worn, but collect data by being in the vicinity of the individual to remotely detect physiological outputs of interest.

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.

Biomarkers

A biomarker is an objectively measured and evaluated characteristic that indicates normal biological processes in the body. Examples of biomarkers include cholesterol for heart health and blood pressure for stroke risk.

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

When we don’t have biomarkers for a disorder, as is the case with Rett syndrome, our ability to assess whether a treatment is working is restricted to the measurement of symptoms and/or improvement in function. Symptom and function improvements can be determined from different types of assessments and biosensors however they could take a relatively long time to improve. The establishment of Rett-specific biomarkers would indicate much earlier if treatments are working by detecting changes at the cellular level by testing bodily fluids and tissues, and testing physiological processes.

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.

Dr. 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.

Jony Saby, PhD and Eric Marsh, MD, PhD

Another potential source for biomarkers is an electroencephalography (EEF), a test that measures the electrical activity of the brain. This project will analyze a dataset of 100 EEG recordings previously acquired as part of the Rett syndrome natural history study and will focus on resting EEG datasets.