RNA binding motifs as therapeutic targets for Angelman Syndrome

Awarded to Mackay Lab, School of Molecular Bioscience University of Sydney
Dates: April 2015 - December 2017
Amount: $332,020

Dr Ingrid Macindoe, under the supervision of Professor Joel Mackay, has entered the second year of a FAST-funded project at the University of Sydney. The team are investigating the role of the UBE3A antisense transcript in silencing paternal UBE3A, using the genome-editing tool CRISPR/Cas9 to make alterations to the antisense transcript and study the effects on UBE3A expression in neurons. They aim not only to uncover the mechanism by which UBE3A is silenced, but also to identify proteins that play a role in this silencing process by interacting with the antisense transcript. Any such proteins could be potential targets for therapeutics.

Ingrid has now successfully finalised the first portion of the project and made cell lines that have a large deletion in one allele of chromosome 15, intended to mimic Angelman Syndrome. She has used Neuro2A cells, a mouse-derived neuroblastoma cell line that grows easily and can be differentiated chemically into neuron-like cells. She is currently testing to ensure that the deletion she has made is in the maternal allele.

These cells should prove a useful resource for the Angelman research community for testing reagents designed to reactivate paternal UBE3A. 

The next steps in the project are; to identify protiens that interact with the Ube3a-ATS and to experiment with the Neuro2A cells to determine if the team are able to affect silencing UBE3A.

Professor Mackay has spoken about the research at the Brisbane 2015 Symposium and Dr Macindoe attended the International Angelman conference in Lison late 2016 to promote her work and the work of the Foundation with our Science Officer Chloe Simons. 

Professor Mackay has also accepted our request to join our scientific advisory team and has already attended some international meetings and is working on new viable approaches for Australian work into Angelman Syndrome including overseeing Ingrid training Ashley Lee, a University of Sydney undergraduate who has signed up to do her fourth year Honours research project in the Mackay lab on the Angelman project. 

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