Gene editing shown to correct rare brain mutations in mice

Amazing stuff! This is just the beginning!

"Scientists have used a single injection to correct gene mutations caused by an ultra-rare disease, improving symptoms and survival rates in mice.

Published in Cell, the gene editing study targeted the 2 most common mutations that cause alternating hemiplegia in childhood (AHC). ..."

"... The new study ... is the first time prime editing has been used to treat a neurological disease in animals, offering hope for treating people with AHC and other genetic brain disorders. Prime editing was developed in 2019  ... The technology has already been successfully tested in a clinical trial for another rare genetic disease. ..."

From the highlights and abstract:

"Highlights

• Prime editing and base editing efficiently correct ATP1A3 mutations in AHC patient cells

• AAV9-delivered prime editing restores Atp1a3 sequence and ATPase function in mice

• In vivo prime editing also strongly rescues behavioral phenotypes and extends lifespan

• Prime editing can serve as a one-time treatment to rescue a neurological disorder

Summary

Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na+/K+ ATPase subunit, cause 70% of AHC cases.

Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models.

We used PE and BE to correct five prevalent ATP1A3 mutations with 43%–90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the CNS of two AHC mouse models, yielding up to 48% DNA correction and 73% mRNA correction in bulk brain cortex.

In vivo PE rescued clinically relevant phenotypes, including restoration of ATPase activity; amelioration of paroxysmal spells, motor defects, and cognition deficits; and dramatic extension of animal lifespan.

This work suggests a potential one-time PE treatment for AHC and establishes the ability of PE to rescue a neurological disease in animals."

Gene editing shown to correct rare brain mutations in mice

Prime editing treats childhood brain disease in mice (original news release) "Scientists use a precise form of gene editing called prime editing to correct the most common genetic mutations that cause alternating hemiplegia of childhood, a rare and severe neurological disorder that begins in infancy."

Mouse models for ultra-rare disorder could pave the way for nervous system gene editing therapies (original news release) "The models offer clear insights into how alternating hemiplegia of childhood progresses—and how it might be stopped"

In vivo prime editing rescues alternating hemiplegia of childhood in mice (open access)

Graphical abstract