New therapy shows promise in LCA disease models

Posted on: Friday 17 August 2018

Researchers in London and the Netherlands have demonstrated the ability of a potential therapeutic molecule, known as QR-110, to help correct the defects associated with the most common disease-causing mutation in Leber congenital amaurosis type 10 (LCA10). Their results have been published in the journal Molecular Therapy: Nucleic Acids.

LCA10 is a severe, early-onset inherited retinal disease associated with inherited changes in the gene CEP290. This gene provides the instructions for building a protein that is essential for the formation and stability of the light sensitive outer segment of photoreceptor cells. A mutation found in 60-90% of people with LCA10 results in incorrect editing and interpretation of the genetic code during protein construction, so that retinal cells end up with a significantly reduced amount of normal, fully functional CEP290 protein.

The research team, including RP Fighting Blindness-supported researcher Prof Mike Cheetham, designed a number of molecules, called antisense oligonucleotides, aimed at silencing the effect of this mutation so that the gene editing machinery can make the correct protein. They found that the molecule QR-110 was most effective at achieving this and was able to restore levels of normal CEP290 protein in cells from individuals with LCA10. In a retina in a dish model made from LCA10 patient stem cells, this resulted in improved photoreceptor structure. QR-110 was also very specific in targeting the mutation without influencing other parts of the genetic code.

The researchers established that QR-110 was well tolerated in animal models, reached all layers of the retina and lasted a suitable length of time in the eye, making it a promising candidate for clinical testing. It has now entered human clinical trial.

Prof Cheetham said “QR-110 has demonstrated clear potential to treat LCA10, and we now need to conduct clinical testing to see if this is reflected in benefits to patients. This approach to treatment could be applicable to a number of other inherited retinal conditions, so these results are an exciting development.”

How your support made a difference
The models used in this research included 3D retinal tissue structures created from special stem cells, known as induced pluripotent stem cells (iPSCs), which are originally derived from the skin cells of people living with LCA. This means that QR-110 and other similar therapies can be tested in a human cell model, avoiding the complications associated with testing in other species. RP Fighting Blindness supports iPSC-based research in Prof Cheetham’s laboratory at the UCL Institute of Opthalmology, something we could not do without your donations.

Read the full paper here.