Advancing therapeutic base editing for vision loss

Objective

Precision gene editing holds immense potential to treat both genetic and non-genetic disorders, representing a paradigm shift in medicine and therapeutics. The eye serves as an ideal model for the development of such innovative therapies due to its accessibility, small size, and relatively immune-privileged environment. Furthermore, most forms of vision loss remain untreatable with conventional medicines, and new treatments are urgently needed. Over the recent years, we have developed therapeutic base editing for the retina, demonstrating exceptional efficacy across multiple in vitro and in vivo models, including large animals. This proposal builds on our previous findings to expand the scope of base editing to new gene targets and tissues, while further advancing its translation to the clinic. In Aim 1, we will focus on novel delivery solutions for base editors. This includes developing improved adeno-associated virus (AAV)-based editors, synthesizing inactivating AAV constructs to mitigate dose-limiting toxicities, and exploring a novel microinjection-based delivery approach. In Aim 2, we will expand base editing to correct a highly prevalent mutation in the CDHR1 gene, which causes macular degeneration. This mutation presents unique challenges due to the absence of canonical binding sites for conventional base editors, necessitating the use of novel engineered editors. In Aim 3, we will extend base editing to the cornea by correcting PAX6 mutations ex vivo in limbal stem cells from aniridia patients, a genetic disease leading to complete blindness. These corrected cells will be transplanted to patients, providing both a therapeutic solution and a unique opportunity to study base editing outcomes in vivo. This project will bridge critical gaps in the application of base editing and establish novel approaches for treating diseases in the eye and will have broad implications in medicine.

Fields of science (EuroSciVoc)

CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.

• medical and health sciences medical biotechnology genetic engineering gene therapy
• natural sciences biological sciences microbiology virology
• medical and health sciences clinical medicine ophthalmology
• medical and health sciences medical biotechnology cells technologies stem cells
• natural sciences biological sciences genetics mutation

Keywords

Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)

• Base editing
• AAV
• gene therapy

Host institution

Beneficiaries (1)