Development of genetic patches for the treatment of hereditary blindness

Genetic errors in genes essential for visual function result in blindness. In this project, Astherna BV and Radboudumc collectively aim to restore retinal function by regulating PRPH2 and/or ROM1 gene expression using gapmer antisense oligonucleotides (“genetic patches” or ASOs).

Hereditary retinal diseases belong to a heterogeneous group of disorders, caused by DNA errors in various genes, which ultimately lead to the malfunctioning and/or death of the light-sensitive rods and cones in the retina. The majority of these diseases are currently still untreatable. One of the genes in which genetic variation frequently results in hereditary vision loss is the PRPH2 gene. Together with the ROM1 gene, it is partly responsible for the construction and functioning of the rods and cones. Dysfunction of the PRPH2 protein affects visual function in an estimated 850 individuals in the Netherlands.

In this project we will test whether we can ensure that the retinal cells function properly again by reducing the expression levels of either the incorrect PRPH2 or ROM1. We do this with the help of so-called Gapmer antisense oligonucleotides (ASOs). These are synthetic DNA/RNA molecules that can specifically bind to a certain transcript (gene product) and thereby regulate its expression.

Upon successful completion, this project will deliver an effective and safe therapeutic ASO that is ready to be tested as a possible new drug for patients with hereditary blindness due to errors in the PRPH2 gene. The safety and effectiveness of this drug will be investigated in selected patients (combined phase I-II clinical trial) by direct administration of the ASO to the eye. If the outcome is positive, these patients can be prevented from eventually becoming blind, which will have a huge impact on their quality of life.