New Prime Editing and non-viral delivery strategies for Gene Therapy

Introduction

Genome editing technologies based on CRISPR/Cas systems allow targeted genomic modification with unprecedented precision and have emerged as powerful alternatives to the conventional gene therapy approaches for various human diseases, with a series of clinical trials in progress. However, some crucial challenges remain to be addressed to enhance efficiency and safety and decrease costs of treatments.

Current Challenges

Current viral-based delivery systems are associated with:

• High risk of toxicity
• Immunogenicity
• High costs

We will develop a new generation of non-viral delivery systems for gene editing tools based on the use of modified nanoparticles with human-derived protein moieties. This approach will allow targeting the tissue and cells of interest in vivo with minimal adverse effects.

Prime Editors

Prime editors have raised exciting possibilities for double-strand break-free genome editing. However, a major limitation of current prime editors is:

1. Highly variable efficiency from one target to another
2. Variability between cell types

We will design and evaluate novel prime editor tools to both increase activity per se and overcome cell-specific limitations.

Application to Sickle Cell Disease

We will test our approach on the hematopoietic system to treat Sickle Cell Disease. This method aims to avoid the challenges and risks of hematopoietic stem cell manipulation associated with current gene therapy approaches, thus providing a treatment that is much simpler, safer, and more cost-effective to implement.

Technological Breakthroughs

Our technological breakthroughs address two key obstacles in cell and gene therapy:

• Gene editing efficiency
• Systemic delivery

The novel prime editors and targeted nanoparticles that we will engineer will be combined to create unprecedented off-the-shelf, recombinant biologics for gene therapy. The versatility of the design of these novel recombinant biologics makes them suitable for the treatment of a vast majority of genetic diseases.