Nanoparticles Treat Degenerative Eye Disease Without Eye Injections

People with macular degeneration develop a blind or blurry spot at the center of their field of vision, making it difficult for them to read and recognize loved ones’ faces. To slow or reverse this loss of vision, many patients receive monthly injections of an antibody drug directly into their eyes. To find a less invasive treatment, a team of researchers led by Balamurali K. Ambati of the University of Utah has tested biodegradable polymer nanoparticles that deliver a therapeutic gene to eye tissue (ACS Nano, DOI: 10.1021/nn305958y). With a single intravenous dose of the particles, the scientists partially restored vision in mice with a model of the disease.

Age-related macular degeneration is the leading cause of blindness among older people in the developed world. In the more severe form of the disease, abnormal blood vessels start to grow in the eyes. These vessels leak blood and plasma into the space underneath the retina, damaging photoreceptor cells and disrupting vision.

Doctors can stop the growth of these blood vessels with an antibody that binds to and blocks vascular endothelial growth factor (VEGF), a protein that stimulates blood vessel production. Because VEGF is needed elsewhere in the body, doctors have to inject the antibodies directly into the eye. Besides the psychological and sometimes physical discomfort of eyeball injections, the treatment can cause infections and lead to detached retinas.

In 2009, Ambati and his colleagues demonstrated that nanoparticles made from poly(lactic-co-glycolic acid) can prevent the release of VEGF (Gene Ther., DOI: 10.1038/gt.2008.185). To get the particles to target affected eye tissue, the team decorated them with a peptide called RGD that selectively binds to receptors expressed in areas of new blood vessel growth. Once inside a cell, the polymer degrades and releases a plasmid of DNA containing the gene Flt23K. This gene inserts itself into the cell’s DNA and then codes for a protein that sequesters VEGF inside the cell so it cannot stimulate blood vessel growth.

Ambati’s team previously showed that these particles could reduce unwanted blood vessel growth in rats that had their retina burned with a laser. The burn triggered abnormal blood vessel growth, but also destroyed photoreceptors, making it impossible for the team to assess how much improvement in vision the therapy could have produced.

As a more realistic test of the therapy, Ambati and his team now have created an animal model of the disease by injecting a virus carrying a short length of RNA into mice. The RNA stimulates blood vessel growth by blocking a naturally occurring VEGF inhibitor. In the current study, the researchers tested their therapeutic nanoparticles in these virus-treated animals.

To assess the animal’s vision, the researchers placed them on a platform surrounded by computer screens. On the monitors, white columns separated by black spaces moved across the mice’s field of vision. The researchers decreased the space between the white columns until the mice no longer responded to the column’s movement. The response the scientists were looking for was a quick jerk of the mouse’s head toward the direction of the moving columns. The better a mouse’s vision, the smaller the separation it could detect.

Six weeks after a single IV injection of the nanoparticles, vision improved significantly in about 85% of the treated animals. These mice responded to separations between bars that were at least 10% smaller than the separations they could detect before treatment. In humans receiving the conventional antibody eye injections, about one third of patients recover most of their vision.

Marco A. Zarbin, a retinal surgeon at the University of Medicine & Dentistry of New Jersey, calls the nanoparticles’ design sophisticated and one that could be used in other regenerative treatments for disease. One concern he has about this specific treatment is whether the nanoparticles might inadvertently target sites of healthy blood vessel growth, such as in the cardiac tissue of heart attack patients.

Ambati says his team is now looking to work with a pharmaceutical company to run further trials on the particles, eventually in people.