ASO for SCN2A gain of function mutation in mice

Title: Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy mode

Affiliation: Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia. Ionis Pharmaceuticals, Carlsbad, California, USA. RogCon Biosciences, Miami Beach, Florida, USA.  Praxis Precision Medicines, Boston, Massachusetts, USA.

Authors: Melody Li, Nikola Jancovski, Paymaan Jafar-Nejad, Lisseth E. Burbano, Ben Rollo, Kay Richards, Lisa Drew, Alicia Sedo, Jacqueline Heighway, Svenja Pachernegg, Armand Soriano, Linghan Jia, Todd Blackburn, Blaine Roberts, Alex Nemiroff, Kelley Dalby, Snezana Maljevic, Christopher A. Reid, Frank Rigo, and Steven Petrou

Reference: J Clin Invest. 2021;131(23):e152079

We thank Dr David Cunnington for providing us with a summary of this study.


What did they do? 

This study tested the effectiveness of a targeted gene therapy for gain of function mutations in SCN2A. Antisense oligonucleotides (ASOs) are designed to specifically target the RNA of interest to deliver a gene therapy. In SCN2A, the aim is to reduce the increased activity of the Nav 1.2 sodium channel in nerve cells that occurs as a function of the SCN2A mutation. 

An ASO treatment was given to mice with SCN2A gain of function mutations either at birth or at 14-16 days after birth to simulate what happens in practice as it takes at least a few weeks after birth for a diagnosis of SCN2A to be made, and compared to what happened when the mice were not treated. 

What did they find?

Mice that were untreated died at day 20 after birth. Those that received a single dose of ASO treatment at birth survived to day 49. If mice were given an additional dose between day 27-30, they survived to day 145. Mice that didn’t receive any treatment until day 14-16 after birth, and only received a single treatment, survived to day 111. 

Effect of ASO given at day 1 (graph A) day 1 and 27-30 (graph B) or at day 14-16 (graph C)

What this means:

This is a really important study as it shows that a gene based therapy of ASO-mediated SCN2A mRNA and protein down regulation was very effective in a mouse model. It very significantly prolonged survival and reduced seizures, and was safe without significant adverse effects. This is a major advance over current treatments which are directed towards symptoms such as seizures alone, but don’t turn off the abnormal gene function seen in SCN2A gain of function mutations. 

How does this move research forward?

This study lays the groundwork for testing this ASO-based gene therapy in humans with SCN2A gain of function mutations. It has been an important study in the development of this novel and highly effective treatment leading to clinical trials which are planned in 2022.