Follow The Leader: Angelman Syndrome #ASO Clinical Trial

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The clinical trial we need to watch, until we have our own.

In the spring of 2020 a much-anticipated clinical trial for Angelman Syndrome using ASO therapy was announced.  (Antisense oligonucleotides:  small single-stranded deoxynucleotides designed to bind to an RNA transcript, to alter the amount of protein produced or to alter splicing forms).  This summer StokeTx published their approach to ASO therapy (called TANGO) for Dravet Syndrome in mice and in June a clinical trial was announced.  Three weeks ago a preprint for an ASO therapy for SCN2A in mice became available.  These announcements are exciting for many reasons, but foremost is what this means for ASO therapy for our Syngapians.


The ASO news is exciting because these three diseases are the first neurodevelopmental encephalopathies to be targeted with ASO therapy.  Early ASO clinical trials failed commercially as small molecule drugs emerged to replace ASO therapy (for HIV CMV-retinitis and familial hypercholesterolemia, in 1998 and 2013, respectively).  More recently, ASO therapy gained popularity as treatment options for degenerative neuromuscular diseases such as Spinal Muscular Atrophy and Duchenne Muscular Dystrophy, both of which have had clinical trials and FDA approvals (Nusinersen/SPINRAZA in 2016 and Golodirsen in 2019, respectively).  And, now ASOs are being developed and are going into clinical trials for treating genetic epilepsies and neurodevelopmental encephalopathies:  Angelman Syndrome, Dravet Syndrome, and SCN2A.  We want to add SYNGAP1 Encephalopathy as soon as possible.


The path to FDA clinical trials can be long and tortuous; but, for rare diseases there can be a silver lining in that many of the steps can occur simultaneously. The paths traveled by the AS, Dravet and SCN2A communities provide a map to follow for the development of ASO therapy for SYNGAP1.  The AS and Dravet communities have been very active in raising funds and driving scientific research.  The AS group FAST recently created a company called GeNeTx and partnered with the leading rare disease pharmaceutical company Ultragenyx to create this ASO and get it to clinical trials.

Before a drug or potential therapy can move into clinical trials, basic principles need to be established such as showing the therapy is effective in the laboratory and in animal models, having clear measures to find out if the therapy helps people, and investigating safety.  Biomarkers need to be established and a natural history study completed.  Each step takes time.  For rare diseases, especially neurodevelopmental diseases, time is precious.  In fact, time is brain.  


Angelman Syndrome (AS) is caused by the loss or dysfunction of the maternal copy of the UBE3A gene, which results in a decreased production of ubiquitin protein ligase E3A in neurons. Clinical signs of AS are similar to SYNGAP1 Encephalopathy and include epilepsy, intellectual disability, gait abnormalities, and global speech and developmental delays.  The ASO in clinical trials is called GTX-102 and it is designed to reactivate the paternal copy of the UBE3A gene, which is naturally silenced by an antisense transcript (UBE3A-AS).  GTX-102 is designed to bind to the UBE3A-AS, which would inactivate the natural antisense and allow protein to be made for neurons in the central nervous system.  The overall effect is to increase expression of ubiquitin protein ligase E3A in neurons.  SYNGAP1 Encephalopathy is a haploinsufficiency and could be treated by increasing expression of SYNGAP1 protein in neurons, similar to the idea for AS.


The current clinical trial for Angelman Syndrome is called  “A Phase I/II Open-label, Multiple-dose, Dose-escalating Clinical Trial of the Safety and Tolerability of GTX-102 in Pediatric Patients With Angelman Syndrome (AS).”   A phase I clinical trial tests a drug or treatment in a small group of people for the first time with the purpose to learn about the safety of the treatment and identify side effects.  A phase II clinical trial tests the therapy in a larger group of people to determine effectiveness and continue to evaluate its safety.  The first patient has been given the GTX-102 ASO.  The current clinical trial is recruiting 20 pediatric patients total. For each individual patient the clinical trial will last about 6 months.  The completion date for these phases is set to be January 2022.  

The trial is described in rich detail here & there is more in the links at the end of this article.

What do we parents need to know?  Here are 5 key takeaways:

  1. GTX-102 cannot theoretically cross the blood brain barrier, so it must be given directly into spinal fluid.  The ASO will be given via lumbar puncture into the intrathecal space or CNS space.  The injection will be given three times total at specific days in time for the study.  
  2. The study has three outcome measures (primary, secondary and other).  The primary outcome measures are to determine the side effects or adverse events and the severity and incidence of the adverse events.
  3. Secondary measures are to determine the total concentration of the drug at specific time points.   The other outcome measures quantify the protein levels in the CSF (only at one time point per the description of the study).  
  4. At the end of the study exploratory outcome measures will determine if the ASO treatment was helpful.  These measures evaluate changes in motor function, development, communication, seizure frequency, sleep, behaviors, and global clinical status. Validated scales and means are required to measure these outcomes for AS.  
  5. Eligible patients will be between 4-17 years old and meet all the screening and inclusion criteria and not meet any of the exclusion criteria. The patient must be healthy enough to undergo multiple lumbar punctures (a.k.a. Spinal taps) and function in the range of the scales for outcome measures or goals.  Please refer to the clinical trial for more information regarding specific inclusion and exclusion


Angelman Syndrome groups have been working for many years to learn the science, raise awareness, raise money and recruit researchers and biopharma companies to create therapies for their children.  Other rare diseases such as Dravet are right behind AS in their quest to start clinical trials for potential treatments.  This is very exciting, because SYNGAP Research Fund (SRF) was founded only two years ago and is not only following the path of these trail blazers, but is “hot on their heels.”  Basic research on SYNGAP1 has been building over the last two decades.  SRF is raising money and recruiting scientists to fill essential gaps in knowledge about SYNGAP1 biology (see SRF’s Pathways to a Cure article).  SRF is connecting with other rare disease groups to learn their strategies and strengthen our community.  And SRF is connecting with biopharma companies to share our children’s stories and find them a treatment.  SRF is working to create a natural history study and establish biomarkers and measurable, validated potential study outcomes.  SRF takes inspiration from Angelman and Dravet Syndrome groups, so when it is our turn for a clinical trial, we will be ready.  And we hope to be next.

Please follow the links below for more information about Angelman Syndrome and the current clinical trial.  Also, below are links to other potential therapies coming soon for rare genetic neurodevelopmental and epilepsy diseases. We can’t wait to hear the results.

For more information about AS and GTX-102:

Other therapies/clinical trials on the horizon to watch closely: