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Angelman Syndrome Dictionary

Glossary of Terms

Adeno-Associated Virus - Gene Therapy (AAV-GT)

A therapeutic approach that is done in-vivo, delivering a healthy copy of the missing or non-functional UBE3A gene using a viral vehicle called an Adeno-Associated Virus to carry the gene directly into the cells of the brain, called neurons.

Allele

One or two versions of a gene at a given genomic location.

Angelman Syndrome (AS)

A rare neurogenetic disorder that affects approximately 1 in 15,000 people – approximately 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.

Antisense Oligonucleotides (ASO)

A therapeutic approach that uses modified RNA or DNA molecules that bind to the RNA of theUBE3A-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 paternal UBE3A gene.

Artificial Transcription Factors/Zinc Fingers (ATF-ZF)

A therapeutic approach that consists of something called “regulatory proteins” which are comprised of modular units that are customized to stop the UBE3A-ATS from silencing the paternal copy of the UBE3A gene, so that it can be expressed in neurons.

Biomarker

A biological marker that is an objective measure of a disease state. This marker can be electrical, like EEG delta power, or molecular, like UBE3A in the cerebrospinal fluid. These markers are aimed to be measured over time so that changes can be documented biochemically or electrophysiologically.

Brain Derived Neurotrophic Factor (BDNF)

A protein that plays a crucial role in learning and memory in the brain. BDNF levels are deficient in AS and serve as a potential downstream targeted therapeutic approach.

Central Nervous System (CNS)

Brain and spinal cord.

Clinical Trial

A research study where investigators test potential ways to detect, treat or prevent a disorder.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)

A gene editing tool that utilizes a guide RNA (gRNA) to recognize DNA or RNA and directs an enzyme to cut a targeted sequence. This therapeutic approach would work to reinstate paternal Ube3a by designing a CRISPR that cuts UBE3A-ATS allowing for paternal gene expression. It can also be used to edit a misspelling in the genome or to activate genes that are halpoinsufficient.

Delivery

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

DNA (deoxyribonucleic acid)

The molecule that carries genetic information for the development and function of an organism. DNA is made of a double helix, which is 2 linked strands that wind around each other and connect by pairs of nucleic acids or molecules and are often coded by the letters: ATCG.

Downstream Targets

A symptomatic therapeutic approach that focuses on different molecular pathways and effector proteins impacted by the missing UBE3A protein.

Dystonia

A neurological movement disorder characterized by involuntary (unintended) muscle contractions that cause slow, repetitive movements or abnormal postures.

E3 Ubiquitan Protein-Ligase Gene (Ube3a) Mouse

The gene that codes for 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.

E3 Ubiquitan Protein-Ligase Mouse Protein (Ube3a) Mouse

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

E3 Ubiquitin Protein-Ligase (UBE3A)

UBE3A is the human protein coded by the UBE3A gene, whose loss is causal of AS. UBE3A is a protein with many functions in the human body including targeting other proteins for removal. 

Note that the human UBE3A protein is capitalized but not italicized. The rodent Ube3a protein is in lower case and not italicized.

E3 Ubiquitin Protein-Ligase Antisense Transcript (UBE3A-ATS)

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

E3 Ubiquitin Protein-Ligase Antisense Transcript (Ube3a-ATS) Mouse

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

E3 Ubiquitin Protein-Ligase Gene (UBE3A)

The gene that codes for the UBE3A protein in humans. UBE3A is located in the 15q11.2-13.1 region and is generally expressed from both the maternal and paternal alleles throughout the body, but in neurons, the cells of 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.

Note that the human UBE3A gene or RNA is capitalized and italicized. The rodent Ube3a gene is in lower case and italicized.

Endpoints

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.

Enzyme Replacement Therapy (ERT)

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

Food & Drug Administration (FDA)

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)

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.

Gene

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.

Gene Editing

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.

Gene Therapy (GT)

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.

Genome

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.

Genotype

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.

Global Angelman Syndrome Registry (GASR)

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.

Hematopoietic Stem Cell - Gene Therapy (HSC-GT)

A therapeutic approach where a patient’s own bone marrow stem cells are removed from the body, modified ex vivo, or outside the body, and returned to the body with a replaced copy of the missing or nonfunctional gene; in this case UBE3A. Once they are injected back into the patient they go to the bone marrow and populate that space with the goal of being released into the system continuously to supply the body with a healthy copy. These cells are able to cross from the blood to the brain, which is called crossing the blood brain barrier. 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 use.

Imprinting

The process by which only one copy of a gene in an individual (either maternal or paternal) is expressed, while the other copy is suppressed or “silenced.”

Induced Pluripotent Stem Cells (iPSCs)

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 type, like neurons. This allows them to be used as tools for testing and research purposes.

International Angelman Syndrome Research Council (INSYNC)

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

Investigational New Drug-Enabling (IND-enabling)

A key milestone prior to clinical testing in humans where various safety, toxicology, pharmacology, and pharmacokinetic properties are determined. These studies help define the properties and de-risk the appropriate therapeutic candidates for a clinical trial.

Maternal

Genetic traits or factors inherited from the mother’s genetics or allele. UBE3A is only expressed from the maternal allele in neurons and the paternal copy is silenced due to the UBE3A-ATS.

Methylation

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. If the methylation test is abnormal, expected genotypes include deletion, UPD, and ICD. If it is normal, a mutation genotype may still be possible after testing the sequency of the UBE3A gene.

Mouse Model (AS Mouse)

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.

Natural History Study (NHS)

An observational clinical study that aims to conduct a prospective, longitudinal natural history study of children and adults with Angelman syndrome using investigator-observed and parent-reported outcome measures to obtain data that will be useful for future clinical trials.

Neurodevelopmental Disorders (NDD)

A group of conditions in which the development of the brain is different from that of neurotypical individuals. This can impact language, emotions, behavior, learning, memory, motor, milestones, and more.

Novel

An adjective that describes something that is new and unique to the research field, for example, a delivery method or therapy.

Observational Clinical Study

A type of clinical study in which participants are identified, observed, and assessed for biomedical or health outcomes. Usually there is no drug introduced into this type of clinical trial.

Observer-Reported Communication Ability Measure (ORCA)

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.

Organoids

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 approaches. For AS, brain cortical organoids have been developed for every genotype.

Outcome Measures

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

Paternal

Genetic traits or factors inherited from the father’s genetics or allele. UBE3A is only expressed from the maternal allele in neurons and the paternal copy is silenced due to the UBE3A-ATS.

Phenotype

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

Pillar 1

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 2

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 3

Pillar of FAST’s strategic roadmap which focuses on different molecular pathways and effector 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).

Pillar 4

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, and driving policy and visibility globally.

Pre-Clinical

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

Rescue

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.

Ribonucleic Acid (RNA)

Ribonucleic acids are the nucleic acids present in all living cells that contain the instruction to make proteins. These molecules are present in a majority of living organisms and are made up of nucleotides, which are sugars attached to bases including the letters: AGUC. RNA is essential for most biological functions and is generally made based on the DNA sequences in the genome through something called transcription. RNA contains the instruction to make proteins.

RNA interference (RNAi)

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

Scientific Advisory Board (SAB)

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.

Synapse

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.

Translational Research

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

Upregulate

A term used in genetics and molecular biology to describe the process of increasing the expression or activity of a gene or protein.

Vector

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.

Wildtype (WT)

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.

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