Department of Ophthalmology

Duke University School of Medicine

Durham, NC

BASIC RESEARCH PROJECT

Development of gene supplementation therapy for PROM1 associated inherited retinal degenerations

Research Interests

Inherited retinal diseases are caused by defects in the genetic code
and result in devastating blindness. Mutations in the prominin-1 gene are well known to
cause severe and irreversible vision loss, for which there is currently no cure. One promising treatment option is gene therapy, which is used to deliver a healthy copy of the mutated gene to the patient’s retina. Gene therapy is a powerful approach that has the potential to stop vision loss, or even partially restore vision. Dr. Alekseev’s laboratory has created a gene therapy for prominin-1 disease and successfully treated the recessive condition in mice. However, prominin-1 mutations often cause a different, dominant type of disease, which may or may not be treatable with gene therapy.

There are many different versions of prominin-1 throughout the human body, and it is unclear which one of them is the preferred configuration of prominin-1 in the human retina. We have identified the most prevalent version of human retinal prominin-1 and used this knowledge to make a gene therapy. Dr. Alekseev deployed this gene therapy to treat a recessive mouse model that lacks prominin-1 and observed a remarkable improvement in retinal anatomy. Encouraged by the success of this gene therapy in the recessive model, the team now seeks to understand whether this gene therapy will also be able to treat dominant disease. Other investigators had previously characterized a mouse model of dominant prominin-1 disease, and their findings strongly suggest that it may indeed be amenable to gene therapy treatment. Therefore, Dr. Alekseev and his team hypothesize that the gene therapy will be able to treat not only the recessive prominin-1 disease but also its dominant counterpart.

Plans for 2025

In 2025, the purpose of the project is to determine whether dominant prominin-1 disease is also amenable to gene therapy treatment.

Specific Aims: To explore the therapeutic scope of this exciting new gene therapy, Dr. Alekseev will create and characterize a mouse model of dominant prominin-1 disease. This model will mimic the most commonly encountered dominant prominin-1 mutation in humans. He will then rigorously test our prominin-1 gene therapy in this mouse model to evaluate the effect of treatment on retinal anatomy and functional vision. These studies have the potential to expand our understanding of the mechanisms underlying prominin-1 dominant disease, and to help identify patient populations that could benefit from prominin-1 gene therapy.

Type of Project: Translational research.