Hurdles to be Overcome for a Trial of Oligonucleotide Therapy in Angelman Syndrome

Quick Overview

Art Beaudet discusses the challenges faced in the trial of Oligonucleotide Therapy in Angelman Syndrome. He highlights the complexity of the knockout mice used in the trials, the potential differences between Angelman genotypes, and the intricate regulation of UBE3A. Beaudet also mentions the difficulties in creating a humanised mouse model for the trials, which has been a significant hurdle. He suggests that Ionis, the company involved, may need to consider alternative strategies. The study has been funded by NIH and the Angelman Foundation.


There are several issues to consider when looking at the potential for oligonucleotide therapy in Angelman Syndrome. One of these is the presence of considerable transcript downstream, as observed in exons 7 and 8 in the null RAT. This is despite the fact that exon 6 is large and contains many methionine codons that could reinitiate.

The RAT and Pneumocystis Infection

The current RAT, interestingly, was infected with pneumocystis carinii at the facility that made the animal. We discovered this and informed them. We are now trying to re-derive the existing RAT to get rid of the pneumocystis infection.

Behavioural Analysis

Rodney Samaco, a faculty member in our department, has developed a plan for more in-depth behaviour analysis of the old Angelman mutation and the new Angelman mutation. Preliminary data shows higher p-values in some of the locomotion tests. There’s also a hint of better distinction between the old Angelman and the new Angelman mutation in the new locomotion foot slip test.

Mouse Behaviour and Phenotype

Mouse behaviour is very challenging to analyse. There may be some lessening of the phenotype in the old Exon 5 compared to the new Exon 6 deletion. There’s much more downstream transcript in the old Exon 5 deletion than in the new Exon 5 deletion. At this point, it’s not clear if in the old mutation, there could be a protein made that has ubiquitin ligase activity.

The Humanised Mouse

Ionis envisions a humanised mouse where a large chunk of the relevant region in the human is inserted into the mouse. This would allow a human ASO to be put into a mouse and activate the paternal copy of the mouse gene. However, this process has proven to be more difficult than anticipated and has slowed down the potential for any Phase 1 trial.

Docking Strategies

There are docking strategies available, such as one published by a group at Stanford and commercialised by a company using the attB and other ATT integration mechanisms. Another strategy involves inserting a loxP and a lox511, a mutant form of a loxP site, into the region.


Angelman Syndrome is extremely favourable for the possibility of a cure by a number of happenstance aspects. However, the knockout mice can be complicated and there may be modest differences between Angelman genotypes. Regulation of UBE3A may be very complex, and getting the humanised mouse to the top level is a priority.

Talk details

  • Title: Hurdles to be Overcome for a Trial of Oligonucleotide Therapy in Angelman Syndrome
  • Author(s): Art Beaudet
  • Author(s)’ affiliation: Baylor College of Medicine
  • Publication date: 2016-09-06
  • Collection: 2016 ASF-Dup15q Scientific Symposium