From Benchside to Bedside: Collaboration Leads to Acceleration for Novel Delivery of CRISPR Technology

Quick Overview

Researchers at Yale University have received a large NIH grant to advance a novel CRISPR-based gene editing delivery platform. The team, consisting of engineers and biologists, aims to deliver the CRISPR system to neuronal cells in the brain using nanoparticles. They have developed a molecule called STEP that can bring the CRISPR system into cells without being trapped in unwanted organelles. The team has demonstrated the effectiveness of the delivery system in cell culture and mouse models, showing significant reactivation of the UBE3A gene. The next step is to conduct IND-enabling studies to evaluate toxicity, target engagement, and overall safety before moving to human clinical trials. The researchers plan to run a first-in-human trial, starting with adult patients and then moving to children. The trial design will follow a standard Phase 1 approach, with a focus on safety and tolerability. The team will use measures and outcomes already established in other Angelman syndrome trials. The ultimate goal is to bring this novel therapy to patients and provide a long-term correction for the disease.

Introduction

At the 2023 FAST Science Summit, Dr. Zhou, Dr. Yong Wei, Allyson Berent, and Dr. Liz Berry-Kravis discussed the recent exciting news about a large NIH grant awarded to Yale University. The grant aims to advance a novel CRISPR-based gene editing delivery platform. This collaboration between researchers and patient advocates is a remarkable example of cross-collaboration and represents a milestone in taking patient advocacy from benchside to bedside.

The Journey of Drug Development

The team discussed the various steps involved in the drug development process for assistive technology. They emphasized the importance of understanding the safety profile, developing endpoints and biomarkers, and running clinical trials. They highlighted the need for community involvement and enrollment in the global registry to ensure the success of these trials.

Novel Delivery of CRISPR Technology

Dr. Jianbing Zhou, an engineer at Yale Medical School, explained his role in delivering the CRISPR technology to neuronal cells in the brain. He discussed the challenges of delivering the CRISPR system, which is large and derived from bacteria, into neuronal cells. He proposed using nanoparticles as an alternate approach to deliver the system to the brain, bypassing the blood-brain barrier. Dr. Zhou also introduced an engineering approach called STEP, which involves chemical modification to enhance the delivery of the CRISPR system into cells.

Preclinical Studies and Animal Models

Dr. Yong-Hui Jiang, a lead expert in the field, presented the findings of preclinical studies and animal models. He showcased the efficiency of the STEP-RNP system in reactivating the UBE3A gene in human neurons derived from Angelman syndrome patient cell lines. The team also demonstrated the effectiveness of the system in mouse models, showing significant correction of behavior phenotypes such as locomotion, memory, and seizure.

Translational Research and Clinical Trials

Dr. Liz Berry-Kravis discussed the next steps in bringing the CRISPR technology from preclinical studies to clinical trials. She explained the rigorous process of IND-enabling studies, which evaluate toxicity, target engagement, off-target risks, and overall safety. Dr. Berry-Kravis emphasized the importance of coordination, time, and funding required for translational research. She outlined the trial design, starting with adult patients and later moving to children, and highlighted the use of validated measures and outcomes from previous trials in Angelman syndrome.

Conclusion

The collaboration between researchers, patient advocates, and institutions has paved the way for the advancement of CRISPR technology in gene editing. The team expressed their gratitude to the NIH, FAST, Yale, and other groups involved in this important collaboration. They emphasized the significance of supporting infrastructure and collaboration in accelerating scientific progress and bringing novel therapies to patients.