Novel Gene Editing Approach for Long-Term Paternal Gene Activation

Quick Overview

Researchers from Yale University School of Medicine presented a novel gene editing approach for long-term paternal gene activation in Angelman Syndrome at the 2022 FAST Science Summit. The approach involves using a protein-based CRISPR system delivered via chemically modified nanoparticles to target and edit the UBE3A gene. The researchers demonstrated that the system efficiently activated gene expression in vitro and in vivo, leading to significant improvements in behavior and motor function in Angelman Syndrome mouse models. The approach shows promise for potential future treatments for Angelman Syndrome in humans.

Introduction

Yong-Hui Jiang and Dr. Jianbing Zhou from Yale University School of Medicine presented a novel gene editing approach for long-term paternal gene activation in Angelman Syndrome at the 2022 FAST Science Summit. Their goal is to find a treatment or cure for Angelman Syndrome and they believe that genome editing therapy holds promise for this purpose.

Three Types of Gene Therapy

The speakers discussed the three different types of gene therapy that can be applied for Angelman Syndrome treatment: gene replacement or gene augmentation therapy, gene suppression using small RNA molecules (sRNA) or antisense oligonucleotides (ASO), and genome editing. They expressed excitement about the potential of ASO-based therapy, but acknowledged its limitations due to its action at the RNA level.

CRISPR-Based Genome Editing

The speakers explained how CRISPR-based genome editing works, using a Cas9 protein and guide RNA to cut the DNA at a specific location. This approach offers the advantage of permanently eliminating the target gene sequence at the DNA level, potentially providing a long-term solution. They discussed the different forms in which CRISPR can be delivered, including DNA, RNA, or protein, and highlighted the potential risks associated with the active nucleus of CRISPR.

Protein-Based CRISPR Therapy

To overcome the limitations and concerns of CRISPR-based therapy, the speakers proposed the use of protein-based CRISPR therapy. They explained that protein-based machinery can be delivered into cells and degrade within 24 hours, reducing the risk of off-target effects. They discussed the challenges of delivering protein-based machinery into cells and presented their research on using polymer particles as an alternative to lipid particles for delivery.

STA Technology for Brain Penetration

The speakers highlighted the limitations of nanoparticle-based delivery systems for neurogenetic diseases like Angelman Syndrome, due to the small intercellular space in the brain. They introduced STA (surface-tailored assembly) technology, a chemical engineering approach that allows for the efficient delivery of therapeutic agents into the brain. They demonstrated the effectiveness of STA technology in delivering CRISPR-based machinery for gene disruption and epigenetic editing, as well as other proteins, ASOs, DNA, and RNA.

Animal Model Studies

The speakers presented their ongoing work on using the novel gene editing approach in animal models of Angelman Syndrome. They showed that the delivery of Cas9 protein and guide RNA using STA technology resulted in efficient gene reactivation and demonstrated significant rescue of behavioral phenotypes associated with Angelman Syndrome. They also discussed the potential for long-term effects and the need for further validation in human models.

Conclusion

Yong-Hui Jiang and Dr. Jianbing Zhou concluded their presentation by expressing their gratitude to the FAST Foundation and the Angelman Syndrome community for their support. They emphasized the importance of collaboration and the need for continued research to develop effective treatments for Angelman Syndrome.