Teaming Up With CRISPR Pioneer Jennifer Doudna to Develop Genetic Medicines for Rett
RSRT awards $1.2M to CRISPR co-inventor and Nobel Laureate Jennifer Doudna and Kai Chen, a researcher in her lab, to explore CRISPR as a way to deliver treatments to the brain for Rett syndrome.
Genome editing tools like CRISPR have the possibility to fix mutations that cause Rett syndrome, with the potential to reduce or even reverse symptoms. But ask any genome editor what the biggest challenge in the field is, and they will tell you in just three words: delivery, delivery, delivery.
RSRT has funded researchers to develop and refine ways to deliver genomic medicines. Late last year, RSRT awarded $1.2 million to CRISPR co-inventor and 2020 Chemistry Nobel Laureate Jennifer Doudna and Doudna lab researcher Kai Chen to refine tools for delivering CRISPR to the brain, with the ultimate goal of creating a CRISPR genome-editing treatment for Rett syndrome.
"We are excited to partner with RSRT on this new project, which taps into one of IGI’s core missions: advancing innovative technologies to treat rare diseases,” says Doudna. “Enabling brain delivery will not only be crucial for treating Rett syndrome, but for a wide range of brain disorders and diseases.”
Monica Coenraads became interested in collaborating with the Doudna lab after reading their February 2024 Nature Communications paper on using CRISPR genome editing in the mouse brain. In the paper, first author Chen and other Doudna lab researchers used cell-penetrating peptides, which are like tiny protein fragments, to deliver the Cas9 protein to the brain without having to rely on a virus to get inside neurons.
“Delivery is a key focus at RSRT and my colleagues and I were excited to learn of Dr. Doudna’s and Dr. Chen’s progress in this area. We wasted no time getting in touch and are delighted that they are now putting their talents and skills to work on behalf of Rett patients,” shared Coenraads.
Through meetings in the summer and fall of 2024, the RSRT and Doudna lab teams developed the idea for the new project. This project, which builds off the 2024 paper, will focus on developing lipid nanoparticles (LNPs) to deliver CRISPR-based therapies to the brain. LNPs are made of lipids, which, like oil droplets, naturally come together to form tiny spheres. Under the right conditions, these spheres can combine around a cargo like a CRISPR protein. And because human cells are surrounded by a lipid membrane, LNPs can naturally connect with them to deliver their cargo, similar to how small oil droplets join together in water.
“One of the big advantages of LNPs over conventional viral delivery is that, unlike viruses, they don’t tend to provoke an immune response,” says Chen. “This also means that a given patient could get multiple different treatments delivered by LNPs throughout their lifetime if necessary, whereas viral treatments can generally only be delivered one time because of immune reactions.”
There are currently at least two clinical trials using LNPs to deliver CRISPR-based genomic therapies to the liver. Early trial results are encouraging, but delivering genomic medicines to the brain is trickier.
“For some brain conditions, like Parkinson’s disease, only a small area is affected and you might be able to deliver the therapy effectively through an injection to that area,” says Chen. “But with Rett syndrome, the entire brain is affected by the lack of functional MECP2 protein. So, our focus is on developing an LNP that can diffuse through the entire brain effectively.”
Chen and Doudna are collaborating with UC Berkeley Professor of Bioengineering Niren Murthy, whose lab focuses on creating novel materials to deliver drugs and genomic therapies.
Ultimately, we hope to create a Rett treatment using base editing,” says Chen. Base editing is a form of CRISPR genome editing that can make small changes to DNA without creating a double-stranded break. The team also aims to develop CRISPR tools to “knock in,” or, add, healthy versions of the MECP2 gene, that could be used to treat patients with any Rett-causing mutation.
