New gene-delivery system can ward off hereditary blindness

A new gene-delivery system for an inherited form of blindness shows promise, according to a recent study.

Researchers at Case Western Reserve University have developed gene-carrying nanoparticles that home in on target cells and prevent vision loss in mice with a human form of Leber congenital amaurosis.

The condition is one of the most common causes of blindness in children, according to the National Institutes of Health, affecting two to three of every 100,000 newborns.

Though this research focused on the form of the disease called Leber congenital amaurosis 2, or LCA2, the scientists and engineers involved in the study believe the technology holds promise for other forms of LCA as well as other inherited diseases that lead to severe vision loss or blindness.

Leader Zheng-Rong Lu said that they believe this technology can deliver almost any type of gene to tackle inherited visual disorders.

Those with LAC2 carry a mutated RPE65 gene and suffer from profound vision loss from birth. The mutated gene fails to produce RPE65 protein in the retinal pigment epithelium (RPE), a cell layer critical for protecting photoreceptors (rods and cones). The protein is an essential constituent of the visual cycle that converts light to electrical signals to the brain.

Lu and colleagues designed a lipid-based nanoparticle called ECO to deliver healthy RPE65 genes to RPE cells.

"The promise of this technology is it localizes the drug to the photoreceptor cells, sparing the liver and kidney from exposure," said researcher Krzysztof Palczewski.

While other researchers focus on using modified viruses to deliver genes for therapy, sometimes the genes are too large for viruses to carry, Lu said. The ECO can be tailored to fit the cargo.

The exterior of the nanoparticle is coated with nucleic acids that act as targeting agents, drawing the delivery system to the retina and facilitating uptake by RPE cells. To track activity, Lu's team included a fluorescent marker

Following injection into the retina of mice, the researchers could see fluorescent green concentrating in RPE cells. Testing showed a significant increase in light-induced electrical activity from the eyes to the brain, indicating the rods and cones were operating as they should in the visual cycle.

The therapeutic effect lasted 120 days in treated mice. No improvements were observed in untreated mice.

The researchers are now investigating whether the ECO system is effective against other visual disorders, including Stargardt disease, which is a form of inherited juvenile macular degeneration, primarily affecting the central portion of the visual field. They are also studying whether the nanoparticles can be used with the CRISPR/Cas9 gene-editing technique to treat genetic lesions related to retinal degenerative diseases.

The study appears in the journal Molecular Therapy Nucleic Acids.