*Disclaimer: All of the summaries published here are only an interpretation by A. Berent of each lecture. None of these lectures were personally transcribed by any of the presenters or companies involved.


The Foundation for Angelman Syndrome Therapeutics (“FAST”) is writing a summary of all of the lectures presented on Friday December 4th, 2015, the first day of the 2015 FAST Global Summit. This lecture series was focused on research, pre-clinical, and future clinical trials. Most of what was discussed is a direct result of the generosity of the Angelman Syndrome community, and we cannot thank everyone enough for their support for this to be possible. This is only the beginning and we are so close to bringing therapeutics to our loved ones with Angelman Syndrome. We hope these brief summaries of each lecture can help each and every one of you feel comfortable explaining all the new information to your families and friends. We will post one lecture summary per week to help break down the information and give you time to absorb the details and ask questions.

Please remember, more research is underway to bring us closer than ever to what we have all been working and waiting for, an effective therapy for our kids! Continue to raise money, as the only way to move things “FASTer” is to further support the research.

Let’s start off by revisiting some simple facts to refresh your memory and then we will get into some of the scientific details:

What causes Angelman Syndrome?

Angelman syndrome (“AS”) is a neurogenetic disorder that results from the lack of function of a gene called UBE3A. This gene is on chromosome 15. We all have 23 pairs of chromosomes (46 chromosomes in total) in each of our cells; we get one from our mother (maternal allele) and one from our father (paternal allele). The gene UBE3A is present on both the maternal and paternal allele in every one of our cells. In neurons (nerve cells) of the brain this gene (UBE3A) is only active on the maternal allele. The paternal allele is “silenced” in the area of the UBE3A coding region. This is due to a “STOP” region that is sitting over the area containing UBE3A. This “STOP” is called the “antisense” or UBE3A-ATS. This blocks expression of UBE3A on the paternal allele, which makes neurons rely solely on the maternal allele for the UBE3A needed in the brain. This process of turning off the gene on one allele is called “imprinting.” Imprinting of UBE3A only occurs in neurons of the brain and not in the rest of the body. UBE3A is read on both the maternal and the paternal strand throughout the rest of the body, but not in the brain where it is only read on the maternal strand. Angelman syndrome occurs when the maternal allele does not function normally resulting in a deficiency in the proteins produced by this gene in neurons. This is either due to a deletion in a region involving this gene (most common, ~70-80% of individuals), a mutation in this gene (~10-15%), there is no maternal strand and the person has 2 paternal strands (UPD-uniparental disomy-both are then turned off in the brain), or there is an abnormality in the methylation of the gene (ICD-imprinting center defect). For more information on the causes of AS, please visit the FAST website. Regardless of the cause, a lack of maternal UBE3A results in the clinical condition called Angelman syndrome.

In Angelman Syndrome, the missing gene is known as UBE3A and the missing protein is known as UBE3A. This gene has many complex functions, many of which are not yet understood completely. This gene encodes a protein called E3A ubiquitin protein ligase (UBE3A or E6-AP), which is responsible for tagging, or “ubiquitination,” of certain proteins. This most commonly marks them for removal. When this gene is missing, this “tagging” process does not happen, and this results in a build up of some proteins that SHOULD have been degraded or removed. There are many important proteins that rely on this ubiquitination function. Proteins in neurons help signals travel in, and between, the neurons to make nerves work and conduct properly. Ubiquitin is used to regulate how some proteins function and can modify proteins to do their jobs more effectively. With the lack of ubiquitination the neurons will not function appropriately or effectively, and this culminates in the condition of Angelman syndrome (AS).

One important protein (that remains in excess because it has not been degraded) that you should understand for the purposes of this review is the GAT1 transporter that normally removes GABA from the synaptic junction. This is important in understanding the therapeutic of OV101 (Gaboxadol). GABA (gamma-aminobutyric acid) is the most important inhibitory neurotransmitter (chemical that allows neurons to talk to each other) in the central nervous system (CNS=brain and spinal cord). GABA plays a very important role in reducing neuronal excitability throughout the CNS, and is also responsible for regulating muscle tone. When GAT1 is in excess, as in Angelman syndrome, it results in reduced levels of GABA at the synapse (or neuron-neuron junction), and subsequently a loss of “tonic inhibition.” This means that the nerves of the brain and spinal cord, and rest of the body, have proteins/neurotransmitters that either inhibit nerve/muscle stimulation (inhibition) or stimulate nerve/muscle stimulation (excitation). The lack of UBE3A disrupts the normal equilibrium and results in “reduced inhibition.” . There are many functions of UBE3A, and the downstream effect this has on different parts of the body and CNS. What you need to understand is that people with AS have a loss of tonic inhibition and excessive excitation and this results in the symptoms we see.

Inhibition is responsible for keeping the body, nerves, and muscles calm; removing excessive excitation/stimulation, or “background noise”, in the brain, which allows for focus, memory, learning, balance, sleep, movement, and organized behavior. If there is too much background noise, and not enough inhibition, what happens is that the balance of excitation and inhibition is not in check and there is too much excitation. This could theoretically result in: seizures; poor motor function; poor balance; poor sleep; poor vision/brain interpretation of what it sees; poor focus; anxiety; etc. This explains many of the clinical signs (phenotype) that are seen with AS. Since the gene UBE3A is missing, essentially tonic inhibition is lacking.

We hope that this general description will assist in understanding the focus of the lectures summarized below and in the following weeks.

What are therapeutic targets for Angelman Syndrome?

There are 3 main approaches to therapeutics that can act in the treatment of Angelman syndrome and FAST is working hard to help improve or develop therapeutic options in all of these areas:

  • DOWNSTREAM=At the level of the proteins, receptors, etc.… that are made or modified by UBE3A, which are missing.
    a. Example of this would be OV101 by Ovid Therapeutics. As Ovid Therapeutics presented, OV101 works on the extrasynaptic GABAA receptor.
  • UPSTREAM=At the level of the gene.
    a. By turning OFF the STOP of the paternal allele=activate the UBE3A that is present but not turned on. Examples include, but are not limited to:i. Drugs like topoisomerase inhibitors [topotecan]; ii. ASO’s [antisense oligonucleotides]; iii. CRISPR or Zinc Finger technology. b. By adding a new copy of a functional UBE3A gene into the neurons so that the missing maternal gene is functionally replaced. i. Examples of this are viral vector strategies, like that presented by Agilis Biotherapeutics.
  • SYMPTOMATIC TREATMENTS=work throughout the body where deficits are located. Examples of these include, but are not limited to:
    a. Antiepileptic or anti-seizure drugs (AEDs);
    b. LGIT diet;
    c. Ketone esters/therapeutic ketones (KES) as presented by Disruptive Nutrition;
    d. Sleep medications;
    e. Gastroesophageal reflux medications;
    f. Constipation medications; and
    g. Therapies (PT, OT, Speech, AAC, etc.…).

Each of these will be expanded upon in each lecture summary. Please keep in mind that the history of AS has progressed quite impressively over the past 2 decades and we should be very excited about where we are headed in 2016:

1998: mouse model of AS created.
2007: AS was cured in the mouse model.
2008: FAST was created.
2011: Viral vector therapy was used for gene therapy to cure AS in the mouse.
2011: Topotecan was found to activate the paternal UBE3A gene
2012: Gaboxadol was found to rescue many symptoms of AS in mice. This human clinical trial is expected to start in 2016.
2015: ASO (antisense oligonucleotide) was found to turn on the paternal UBE3A gene by turning off the stop of the ATS and rescues many of the symptoms of AS in mice.
2015: Zinc Finger technology was used to show expression of UBE3A in the entire brain of mice with a peripheral injection.
2015: Rat model of AS created for better pre-clinical testing of therapies.
2015: 35/17,000 compounds investigated in a drug library were found to potentially turn on the UBE3A gene, all of which are currently being further evaluated for accuracy.
2015: Pigs pregnant with AS piglets and expect first delivery in early 2016 for better pre-clinical trials.
2015: Ketone esters/therapeutic ketones found to rescue many symptoms of AS in mice and this human clinical trial is expected to start in 2016.
2016: The sky is the limit!!!!