Changing the Channel

Leber’s Congenital Amaurosis (LCA) affects up to one in every 30,000 children. The result of mutations in as many as 20 genes encoding retina specific proteins, LCA causes severe visual impairment and is incurable. Working towards a solution, researchers at the University of Wisconsin School of Medicine and Public Health have found two possible ways to correct KCNJ13 – the mutant gene behind LCA16 (1).

The group created a ‘disease-in-a-dish’ model from a skin biopsy sample collected from a LCA16 patient with a view to test two possible approaches. Bikash Pattnaik, Associate Professor of Ophthalmology and Visual Sciences and lead author, explains the study: “Unlike traditional approaches, where you compare a mutated cell type with a normal cell, we compared the mutated cell type with iPSC-RPE generated from a normal family member. This comparison takes all common factors between the two individuals into account and only reflect one absolute cause of blindness.”

Both cells appeared normal in structure but, explains Pattnaik, “Our study showed that the only difference between the diseased and control cells was a defective potassium ion channel.”

“We have previously shown that these channels are crucial for communication between light-sensitive photoreceptor neurons and RPE cells; a defective channel will thus not permit detection of light by the retina.”

First, the team tried to ‘rescue’ the deficient ion channel with readthrough drug therapy. Promisingly, some of the ion channel function was restored. Next, Pattnaik and his team tried lentiviral gene delivery. “It’s a simple approach in theory but, practically, there are several caveats,” says Pattnaik. “These proteins need to be made from the new gene, assembled correctly and trafficked to the cell membrane – and all completely functional. We knew that even 25 percent recovery would be sufficient to cure blindness but in this particular case, therapeutic gene therapy recovered the function by more than 50 percent,” says Pattnaik.

The team hopes the findings could lead to a future LCA treatment, and believe a similar approach could be used to tackle other ion channel diseases, such as neuropathies and cardiac diseases.

In the meantime, Pattnaik wants to share a broader message: “It’s important to convey that, in this era of precision medicine, we absolutely need to firm up the relationship between the patient, providers, and researchers.”