Angelman Syndrome Dictionary

A therapeutic approach where a healthy copy of a virus, Adeno-Associated Virus (AAV), is used to carry a healthy copy of a gene to a target organ. This is most commonly delivered in-vivo (inside the body). For Angelman syndrome (AS) the healthy copy of the missing or non-functional UBE3A gene is packaged inside the AAV, and is injected into the fluid that surrounds the brain, called the cerebrospinal fluid (CSF). Once in the fluid, the virus and gene can directly reach important cells of the brain, called neurons, and replace the non-functional or missing copy of the gene.

A specific version of a gene. Each individual has two alleles for each gene, one inherited from their mother and one from their father.

A rare neurogenetic disorder that affects approximately 1 in 15,000 people – or an estimated 500,000 individuals worldwide; a single-gene disorder caused by loss of function of the UBE3A gene on the maternal allele located in the 15q11.2-13.1 region.

A therapeutic approach that uses modified RNA or DNA molecules that bind to the RNA of the UBE3A-ATS (UBE3A antisense transcript). The UBE3A-ATS is responsible for silencing the paternal UBE3A gene through a process called imprinting. In binding to the targeted antisense transcript, the ASO stops the UBE3A-ATS from silencing the expression of the paternal UBE3A gene.

A therapeutic approach that consists of using engineered proteins designed to regulate gene expression in a highly specific manner. They are constructed to bind at specific DNA sequences and can either activate or repress the expression of target genes. ATF-Zinc fingers are small proteins that use zinc ions to stabilize their structures giving them a finger-like appearance. ATF-ZFs can bind to the UBE3A-ATS and prevent the silencing of the paternal copy of the UBE3A gene.

A biomarker (biological marker) is a measurable indicator in the body that helps assess the presence of a disease or monitor the effectiveness of a treatment. Examples in AS could include changes in brain activity (i.e. EEG) or changes in blood or other body fluids (e.g. levels of certain proteins like UBE3A in the CSF). To be used in a clinical trial, biomarkers must be validated to prove that they are reliable, associated with a specific symptom or condition, and work in many different individuals living with the condition. Validated biomarkers can provide objective evidence of that a potential therapy is improving a condition or symptom.

A tightly locked layer of cells that act as a filter and protect your brain from harmful substances, infections (e.g. virus) and other things that could cause damage. It also helps to keep beneficial chemicals inside the brain. It's a key part of maintaining brain health and isolating the brain for chemicals and substances that travel throughout your blood. Due to this protective layer, it is difficult to get large substances across it from the blood and into the brain.

A protein known to be reduced in AS that plays a crucial role in synaptic function and is essential for the process underlying learning and memory. BDNF exerts its effects by binding to specific receptors on the surface of neurons, mainly the TrkB (Tropomyosin receptor kinase B) receptor. The BDNF-TrkB receptor represents a potential downstream therapeutic target.

The CNS is the majority of the nervous system including the brain and spinal cord.

A clear colorless body fluid found in the space that surrounds the brain and spinal cord. CSF is produced by specialized cells, called ependymal cells, in the blood vessels (choroid plexus) of the ventricles of the brain. This fluid is being turned over and replenished throughout the day.

A scale, typically completed by an expert health care provider, that provides a rating of overall illness severity, improvement and response to treatment.

A clinical trial is a prospective research study, generally on human participants, designed to answer specific medical questions. This includes both interventional trials to evaluate the safety, effectiveness, and side effects of any form of a medicine in human patients or observations trials to evaluate the function of individuals over time (e.g. natural history study [NHS]).

A gene editing tool that utilizes a guide RNA (gRNA) to recognize a specific section of DNA or RNA and directs an enzyme (nuclease) to cut at a specific section in the DNA or RNA. Designing a CRISPR that affects the UBE3A-ATS could potentially allow the paternal UBE3A gene to be turned on. It could also be used to edit a mutation in a gene, known as base editing.

A gene modulation technology that utilizes a nuclease-deactivated Cas9 protein that binds to the target genomic region with the same efficiency as Cas9, but does not cut the DNA and instead can exert RNA-directed transcriptional control of the targeted gene with a goal to upregulate a specific gene.

The mechanism in which a therapeutic is transported to the central nervous system of the body; delivery includes the route of administration (e.g. brain, spinal cord, blood vessels, bone marrow, etc.) and how the therapeutic reaches its target location (e.g. carrier of the therapeutic like viral vector, bone marrow stem cells, RNP, etc.).

The molecule that carries genetic information for the growth, development and function of an organism. DNA is composed of four chemicals, which are abbreviated A, T, C, and G (A=adenine, T=thymine, C=cytosine, and G=guanine). Segments of the DNA, called genes, provide the instructions for proteins, with the ACTG chemicals making up the code for the protein. DNA has two strands of the chemicals that wind around themselves to form a double helix.

A therapeutic approach in Angelman syndrome that focuses on different molecular pathways and effector proteins impacted by the missing or non-functional UBE3A protein.

A neurological movement disorder characterized by uncontrolled (involuntary) muscle contractions that cause repetitive or twisting movements or abnormal postures.

UBE3A is the human protein coded by the UBE3A gene. Absence or loss of function of UBE3A causes AS. UBE3A is a protein with many functions in the human body including targeting other proteins for removal.

The long, noncoding piece of RNA that blocks paternal UBE3A gene expression in humans.

The long noncoding piece of RNA that blocks paternal Ube3a expression in rodent models.

The gene that codes for the UBE3A protein in humans. UBE3A is on chromosome 15, in the 15q11.2-13.1 region and is generally expressed from both the maternal and paternal copies throughout the body. In neurons (cells of brain), only the maternal copy of the UBE3A gene is expressed. This is called imprinting. The UBE3A-ATS is silencing the paternal UBE3A gene from being expressed.

The gene that codes for the Ube3a protein in rodents. Ube3a is generally expressed from both the maternal and paternal alleles throughout the body, but in neurons, the cells of the brain, only the maternal copy of the Ube3a gene is expressed. This is due to the imprinting phenomenon where the Ube3a-ATS is silencing the paternal Ube3a gene from being expressed.

Ube3a is the rodent model protein coded by the Ube3a gene. The Ube3a protein has many of the same functions as the human UBE3A protein. The conservation of function between humans and animals allows researchers to use the AS animal model and test therapeutic efficacy.

Quantitative and/or qualitative measures that can be assessed in a clinical trial based on the symptoms of a disorder like communication, sleep, behaviors, motor function, etc.

A therapeutic approach replacing the missing or nonfunctional UBE3A protein in the brain.

A government agency in the USA that is responsible for protecting the public’s health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products (like cell and gene therapies), medical devices, food supply, cosmetics, etc.

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the brain that plays a crucial role in regulating brain activity. GABA‘s primary function is to inhibit or reduce the excessive firing of neurons, which can lead to overstimulation and conditions like anxiety, stress, and even seizures.

A segment of DNA that can code for a specific protein. When genes are missing or letters are misspelled, this can lead to a nonfunctional or nonexistent protein.

A technology that allows one to change or edit parts of the genome, either the DNA or the RNA. This can be used to create tools that mimic genetic disorders, and can also be used to correct certain genetic disorders. This results in either the removal of existing DNA or RNA or the insertion or replacement of DNA or RNA.

A therapeutic approach that involves introducing, modifying or replacing specific genes within target cells with the goal of correcting or compensating for a genetic condition, resulting in the absence or loss of function of a gene.

A complete set of an organism’s genetic material, including all of its genes. This serves as a genetic blueprint or instruction manual for the growth, development, functioning, and reproduction of that organism; the genome is encoded in the DNA (deoxyribonucleic acid) of an organism’s cells.

Refers to the specific genetic makeup or combination of genes that an individual organism possesses. AS has 5 genotypes: Deletion, Mutation, UPD, ICD, and Mosaic.

A registry that assists pharmaceutical companies in understanding the scope of AS based on the data contributed by those who know the patients best: caregivers.

A therapeutic approach where an individual’s own bone marrow stem cells are removed from their body, modified ex vivo, or outside the body, and returned to the body with a replaced copy of the missing or nonfunctional gene (UBE3A in this case). Once the bone marrow cells are injected back into the individual, they go to the bone marrow to grow and repopulate. The goal is for those cells to continuously supply the body with a healthy version of the gene. These cells can cross from the blood to the brain, which is called crossing the blood brain barrier (BBB). Once they cross the blood brain barrier, they become a cell type called microglia and secrete the UBE3A protein throughout the brain for neurons to take up the protein and use it.

The process by which only one copy of a gene in an individual is turned on, based on whether the gene was inherited from the mother or the father. The copy from the other parent is turned off or “silenced.”

A genotype of AS that is caused by an error in imprinting, either as a result of a random event at the imprinting center or because of an imprinting center deletion. This results in silencing of both the maternal and the paternal copies of UBE3A and therefore lack of expression of the UBE3A gene or protein.

iPSCs are derived from mature cells in the body, like skin or blood, and can be reprogrammed back into very young cells enabling them to grow into a determined cell lines, like neurons. This allows them to be used as tools for testing and research purposes.

A council that brings together world experts in and outside of the Angelman syndrome ecosystem to help support advancing AS drug development, ensuring all research avenues are identified, de-risking novel therapeutic platforms, and encouraging collaborative efforts within the field of neurogenetic disorders.

Research experiments performed in animals and cells to study safety, toxicology, pharmacology, and drug metabolism of a potential therapy. These studies are required by the regulatory organizations, like the FDA, to help define the properties, define the dose, and reduce risks of potential therapies before the potential therapy is provided to humans in a clinical trial.

Genetic traits, variants or chromosomes inherited from the mother. UBE3A is only expressed from the maternal copy of the 15th chromosome in neurons and the paternal copy is silenced due to the UBE3A-ATS.

Methylation is a chemical modification of DNA that can affect gene expression. Methylation testing is a common type of diagnostic testing in AS used to determine if UBE3A is abnormally methylated. Methylation testing can detect deletion, UPD, and ICD genotypes. The mutation genotype is not identified on methylation testing.

This therapeutic approach utilizes specific pieces of RNA, called micro-RNA, that are delivered in an AAV virus to the brain, aimed to bind to the UBE3A-ATS and activate the silent paternal copy of the UBE3A gene in neurons.

The mouse is the foremost mammalian model for studying human disease. Several mouse models of AS exist, which have been able to recapitulate many of the symptoms like balance disorders, anxiety, learning and memory challenges, motor dysfunction, increased seizure susceptibility, and an abnormal EEG.

An observational clinical study that aims to conduct a prospective, longitudinal evaluation of children and adults living with Angelman syndrome using investigator-observed and parent-reported outcome measures, or endpoints, to obtain data that will be useful for future clinical trials. Understanding how individuals perform on these measures without a potential therapy can help to guide if that trajectory of development can change after a therapy is given.

A group of conditions that are associated with differences in brain development. This can impact language, emotions, behavior, learning, memory, motor function, and more.

Something that is new and unique to the research field, for example, a delivery method or therapy.

A type of clinical study in which participants are identified, observed, and assessed for biomedical or health outcomes. Usually there is no drug or intervention in this type of study (e.g. Natural History Study).

A caregiver reported outcome measure that separates communication into three main concepts: expressive, receptive and pragmatic communication. This measure was developed by FAST in collaboration with Duke University for AS specifically and is now being advanced for 14 other rare NDDs. The ORCA is now being assessed in all active clinical trials for AS and is the first validated endpoint specially developed for the AS population.

Three-dimensional tissue cultures that are derived from stem cells. Organoids are self-organized cultures that can be crafted to replicate much of the complexity of an organ to characterize and test various therapeutic modalities. For AS, brain cortical organoids have been developed for every genotype.

A measure, or test, to determine if a potential treatment or intervention has an effect. Typically, this assessment is collected before a treatment/intervention for baseline results, then re-administered after the treatment/intervention to measure for changes due to intervention.

Genetic traits, variants or chromosomes inherited from the father. UBE3A is only expressed from the maternal copy in neurons and the paternal copy is silenced due to the UBE3A-ATS.

An individual’s observable characteristics resulting from their genotype. In AS this can be their ability to walk, talk, sleep, have seizures, etc.

Pillar of FAST’s strategic roadmap which focuses on replacing the missing or non-functional maternal copy of the UBE3A gene or protein in neurons of the brain. This includes therapeutic platforms like AAV-GT, HSC-GT, ERT, etc.

Pillar of FAST’s strategic roadmap which focuses on activating the silent copy of the paternal UBE3A gene in the brain. This includes therapeutic approaches like ASOs, CRISPR, ATF-ZF, miRNA, etc.

Pillar of FAST’s strategic roadmap which focuses on different molecular pathways and proteins impacted by the missing UBE3A protein. These drugs generally aim to improve the communication of neurons at the synapse (junction between the two neurons) and are often referred to as downstream targets.

Pillar of FAST’s strategic roadmap which focuses on work supporting necessary research tools, clinical developments, and community efforts to prepare for AS clinical trials and drug approvals. This includes the development of a clinical trial training centers, newborn screening efforts, advancing endpoints and biomarkers (A-BOM), and driving policy and visibility globally.

Refers to any research investigating a potential therapeutic approach prior to clinical assessment in humans.

Refers to a technique or experimental approach aimed at restoring or improving a specific biological function or phenotype that is disrupted in a genetic or disease model.

The molecule that translates genetic information from DNA into proteins. Unlike DNA, RNA is usually single-stranded and helps carry instructions from the genes to the cell's machinery that makes proteins. RNA is composed of four chemicals, abbreviated A, G, U, and C.

A natural cellular process that helps control gene expression. RNAi occurs when small RNA molecules inhibit or reduce the expression of a particular gene(s).

A group of FAST volunteers made up of scientists and clinicians who review grants, advise on new scientific ideas, and support ongoing programs in academia and industry.

A low molecular weight compound that is small enough to easily get into tissues, enter cells, and interact with specific biological targets. In AS, small molecules could be developed that function as drugs by modulating biochemical pathways, inhibiting or activating specific proteins, or altering cellular processes shown to be altered in AS neurons. These targets of small molecules can be proteins, DNA, RNA or the ATS.

A neuronal junction, which is the site of electric nerve impulse communication between two neurons or between a neuron and a muscle cell. This junction is impacted in AS.

The process of turning observations in the laboratory, clinic, and community into interventions that improve the health of individuals.

The process of increasing the expression or activity of a gene or protein.

A delivery system or carrier used to transport therapeutic agents, such as gene therapies, vaccines, or other medical treatments, to their intended target within a patient’s body. Terms you might hear are Adeno-associated Virus Vector or Lentiviral Vector.

When animal models are designed, the WT genotype refers to an animal without any mutated genes. The phenotype of a WT mouse is considered to be “typical” functioning and can be used as a comparison group for animals with the mutated gene, or the AS model.