New form of gene editing for macular dystrophies

Dr Forbes Manson, University of Manchester - £106,474

This project investigated whether a new approach to gene editing, called CRISPR-activation (CRISPR-a), could be used to treat inherited macular dystrophies. Rather than correcting individual gene mutations, CRISPR-a increases the activity of a gene, helping cells produce more of the protein it provides instructions for. This could potentially be used to treat a wider range of mutations and patients.

What was the problem?

Macular dystrophies (MDs) can be caused by mutations in many different genes, as well as different changes within the same gene. This makes it difficult to develop gene therapies that are suitable for a wide group of patients, as many current approaches need to be designed for a specific genetic change.

These highly targeted therapies may only be suitable for a small number of patients, which can also make them expensive to develop. A treatment approach that could be adapted to work across a wider range of genetic changes is therefore needed.

Many of the gene mutations that cause macular dystrophies reduce gene expression, meaning less of the relevant protein is produced, or result in a protein that does not work as effectively as it should. CRISPR-a can increase gene expression, encouraging cells to produce more of the protein. Because it does not target a single specific mutation, it could potentially be used to treat a larger group of patients.

What did the project achieve?

The team used CRISPR-a on genes commonly associated with macular dystrophies, including ABCA4, which is associated with Stargardt disease, and BEST1, which is associated with Best disease.

They developed several guide RNAs to direct CRISPR-a to the correct gene. Many performed very well, increasing gene activity by up to 60 times in laboratory-grown cells. This demonstrates the potential of CRISPR-a as a future treatment approach for inherited retinal diseases.

The team also developed laboratory models of disease using cells donated by patients with Stargardt disease, autosomal recessive bestrophinopathy (ARB) and CRB1-related macular dystrophy. The cells were reprogrammed into stem cells and then developed into retinal tissues that closely resemble those found in the human eye.

These patient-derived models provide a valuable way to study how different macular dystrophies develop and to test potential new treatments. Comparing the patient-derived tissues with healthy tissues also revealed important differences in gene activity and cell structure, providing new insights into how these diseases cause vision loss.

What's next?

The project has advanced the development of human-based models for inherited macular dystrophies and established a strong foundation for future research.

In the longer term, this work could contribute to the development of gene-based treatments designed to preserve vision in people with inherited retinal diseases.