A Natural History Study of Angelman Syndrome

A Longitudinal Natural History Study of Adults and Children With Angelman Syndrome

The goal of this observational study is to learn about the natural progression of Angelman syndrome (AS) in children and adults with a confirmed genetic diagnosis of AS. The main questions it aims to answer are:

• How do developmental skills, such as communication, motor abilities, and adaptive behaviors, change over a 1-year period in people with AS?
• Are there specific patterns in brain activity or sleep that are associated with changes in AS symptoms over time?

Participants will:

• Attend 3 in-person and 2 virtual study visits over 1 year for assessments.
• Complete tests and questionnaires about development, behaviors, and sleep with the help of their caregivers.
• Undergo electroencephalograms (EEGs) to measure brain activity and wear a sleep-monitoring device at home (to collect actigraphy data).

• Longitudinal, natural history study of 40 individuals with AS, enriched for a child and adolescent population.
• Seeks to establish normative data to inform future design and interpretation of clinical trials for AS and to support the development of more precise diagnostic tools and targeted therapeutic interventions for AS.
• Track adaptive behavior, communication, challenging behaviors, general health, overall disease severity, and common co-occurring conditions (including epilepsy and sleep disturbances) through standardized assessments.
• Biomarker data collected through EEGs and actigraphy recordings will be analyzed to assess age-related changes in clinical outcomes and neurophysiological measures.
• Participants will attend up to 5 study visits over the course of 12 months: Week 0, Week 13, Week 26, Week 39, Week 52. Weeks 0, 26, 52 will be in-person. Weeks 13 and 39 will be remote.

Inclusion Criteria:

• The participant has a primary clinical diagnosis of Angelman syndrome with documented genetic variation(s) affecting the function of the UBE3A gene within the human 15q11.2-q13.3 locus. Co-occurring conditions (e.g., autism spectrum disorder, cerebral palsy, intellectual disability) are permitted; however, Angelman syndrome must be the primary clinical diagnosis.
• The participant is male or female (assigned sex at birth) and aged ≥1 year at the initial study visit.
• The participant has a study partner who meets the study partner criteria below.
• The participant, if unable to provide informed consent, has an appropriate surrogate who is at least 18 years of age and willing and able to provide informed consent on behalf of the participant in accordance with current International Council for Harmonisation (ICH) guidelines and applicable institutional regulations.

Individuals must satisfy the following criteria to be enrolled as study partners:

• The study partner is a parent or primary caregiver who is at least 18 years of age.
• The study partner has consistent contact with the participant and, in the opinion of the investigator, is sufficiently knowledgeable about the participant's ongoing condition to provide accurate and current information.
• The study partner has sufficient English-language proficiency to complete study partner assessments.
• The study partner is willing and able to provide informed consent on their own behalf in accordance with ICH guidelines and applicable institutional regulations.
• The study partner is, in the opinion of the investigator, reliable and competent; willing and able to accompany the participant to all study visits and comply with study procedures; reachable by telephone or email as needed; and sufficiently knowledgeable about the participant's ongoing condition(s) to provide accurate and current information regarding the participant's health and well-being.

Exclusion Criteria:

• The participant has at least one additional known genetic abnormality outside the human 15q11.2-q13.3 locus causing a probable or known developmental disability.
• At least one standard-of-care treatment (medication or adjunctive therapy) used by the participant was changed during the 28 days (4 weeks) prior to the first study visit. Treatments include, but are not limited to, doses of anti-epileptic medications, behavioral management medications, sleep medications, gabapentin, cannabidiol, special diets, supplements, speech therapy, occupational therapy, applied behavioral analysis (ABA), psychosocial interventions, physical therapy, or nutritional support.
• The participant has unstable epilepsy, defined as having an emergency department visit or hospitalization for seizure-related concerns within the 28 days (4 weeks) preceding the initial study visit.
• The participant is of childbearing potential and is either pregnant, breastfeeding, or not using an adequate method of contraception; abstinence is acceptable.
• The participant has a clinically relevant history of malignancy; clinically significant abnormal test results; clinically significant cardiovascular, hematologic, hepatic, muscular, neurologic, or renal disease; or has experienced other clinical events which, in the opinion of the investigator, render participation unsuitable.
• The participant has a lifetime history of treatment with any cell- or gene-based therapy, including antisense oligonucleotides or gene-editing therapies.
• The participant has received any investigational therapy other than a cell- or gene-based therapy within 28 days or 5 half-lives (whichever is longer) preceding the initial study visit.
• The participant is currently enrolled or plans to enroll in an interventional study involving an investigational agent or device during the planned observation period.
• The participant has a known contraindication to electroencephalography, actigraphy, or any other study procedure described in the schedule of assessments.
• The participant or study partner is, in the opinion of the investigator, unsuitable for participation in any other way, including an inability to fulfill study requirements.