Advancing Usher syndrome type 1B gene therapy with split intein

Project Aim

Usher syndrome is the leading cause of combined deafness and blindness in the world. Usher syndrome type 1B (USH1B) is associated with mutations in the MYO7A gene. Although the FDA has approved adeno-associated virus (AAV) for other genetic diseases like voretigene neparvovec (LuxturnaTM) for retinitis pigmentosa, a single AAV cannot deliver the large MYO7A gene needed for treating USH1B due to AAV’s packaging limitation. Using two AAV vectors to deliver the MYO7A gene in halves at RNA level has shown limited success. Protein trans-splicing, which efficiently joins split proteins, is a promising solution. Our study aims to show effective MYO7A protein reconstitution by finding the best split site in the gene. We aim to deliver full-length MYO7A protein in a USH1B mouse model using intravitreal injection. This less invasive administration method ensures wider vector spread in the retina compared to traditional subretinal injection, utilizing our new AAV vectors.

Project Summary

This project focused on developing a better gene therapy approach for Usher syndrome type 1B, an inherited condition caused by faults in the MYO7A gene. A major challenge in treating this disease is that the MYO7A gene is too large to fit inside the small viral delivery tools commonly used in gene therapy, called AAV vectors. Another challenge is getting the treatment into the right cells in the retina, especially the light-sensing cells known as photoreceptors. In this project, we tackled both problems at the same time. We worked on a way to split the large MYO7A gene into
two parts so it could be delivered more effectively, and we also developed an improved AAV vector designed to reach photoreceptors more efficiently through a simple injection into the eye. This work is aimed at creating a safer, less invasive and more practical path toward future gene therapy for Usher syndrome and other inherited retinal diseases caused by large genes.

Research Impact and Significance

For people living with inherited retinal diseases, one of the greatest frustrations is that many promising genes are still considered too difficult to treat. Large genes such as MYO7A have remained especially challenging because they do not fit neatly into current gene therapy systems. This project helps move that barrier. By showing that MYO7A can be split more effectively and delivered using a better retinal vector, we have taken meaningful steps toward a future treatment that may be safer, less invasive and more effective. While more work is still needed before this can reach patients,
these results provide a strong foundation for the next stage of testing in animal models and for longer-term translation toward human treatment.

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