Study advances gene therapy for glaucoma

January 16, 2018 by David Tenenbaum, University of Wisconsin-Madison
In an effort to improve gene transfer to treat the blinding disease glaucoma, the front of an untreated eye (left) is compared to an eye (right) pretreated with a gene delivery enhancer. The green marker reveals the expression of a new gene in the trabecular meshwork, which drains fluid from the eye and is usually blocked in glaucoma. The green band resulting from gene transfer is denser and wider in the enhancer-treated eye. Credit: Curtis Brandt/Paul Kaufman, University of Wisconsin-Madison

While testing genes to treat glaucoma by reducing pressure inside the eye, University of Wisconsin-Madison scientists stumbled onto a problem: They had trouble getting efficient gene delivery to the cells that act like drains to control fluid pressure in the eye.

Genes can't work until they enter a cell.

Glaucoma, one of the most common blinding diseases, is caused by excess pressure inside the eye, usually due to a clog in the fluid drain. "Most glaucoma can be treated with daily drug treatment," says Paul Kaufman, professor of ophthalmology and visual sciences at the University of Wisconsin-Madison. "Replacement could, theoretically, restore normal fluid flow for years on end, without requiring daily self-administration of eye drops that is inconvenient and may have local or even systemic side effects."

In a study published today in the scientific journal Investigative Ophthalmology and Visual Science, Kaufman and Curtis Brandt, a fellow professor of ophthalmology and visual sciences at UW-Madison, showed an improved tactic for delivering new genes into the drain, called the trabecular meshwork.

The colleagues have been testing a vector based on feline immunodeficiency virus (FIV) to deliver the genes. Like the related , FIV can insert genes into the host's DNA. The eye's innate defenses against FIV, however, interfered with the delivery.

Virus particles contain genes wrapped in a protein coat and then a lipid membrane. After the virus enters the cell and sheds its membrane, defensive molecules from the host can "drag the virus particle to the cell's garbage disposal, called the proteasome, where it is degraded," Brandt says. "We wanted to know if temporarily blocking the proteasome could prevent the destruction of the gene delivery vector and enhance delivery."

In the current study, FIV virus carrying a marker protein was placed on cells of the trabecular meshwork, with or without a chemical that blocks proteasomes.

Above a dosage threshold, the treatment roughly doubled the transfer of genes entering the target cells, Brandt says. The new genes also spread more uniformly across the meshwork tissue. Delivering more copies of the gene should give a greater therapeutic effect, opening the meshwork drain and reducing pressure inside the eye.

The present study concerns the tools for transferring genes, not the genes themselves, Brandt says. But even before the current study, he says he and Kaufman "have already identified at least two genes that could unplug the drain."

In the long struggle to replace genes and cure disease, "eyes have been one of the big success stories," Brandt says. A blinding eye disease called Leber's congenital amaurosis damages the function of cells that keep the light-sensitive healthy; replacing the mutated genes has preserved and even improved vision in young patients. Approval for this gene therapy is now pending at the Food and Drug Administration.

To forestall danger from injecting a virus, "We take out pretty much all of the ' genes, so it has no chance to replicate and spread from where it's initially injected," says Brandt.

Although the technique does interfere with the anti-viral defense in the eye, the effect is temporary. "You encounter the drug once, then it is metabolized, and the innate inhibition is lost," Brandt says.

"We have shown that this strategy does work in eye organ culture," Brandt says. "Once we do further work on efficiency and identify which gene to deliver, then we are probably ready to move toward clinical trials."

Explore further: Genetic treatment for blindness may soon be reality

Related Stories

Genetic treatment for blindness may soon be reality

November 11, 2017
Patients who had lost their sight to an inherited retinal disease could see well enough to navigate a maze after being treated with a new gene therapy, according to research presented today at AAO 2017, the 121st Annual Meeting ...

Study in mice suggests stem cells could ward off glaucoma

July 26, 2016
An infusion of stem cells could help restore proper drainage for fluid-clogged eyes at risk for glaucoma. That's the upshot of a study led by a Veterans Affairs and University of Iowa team.

Potential drug target identified for Zika, similar viruses

June 17, 2016
Scientists potentially have found a way to disrupt Zika and similar viruses from spreading in the body.

Protein critical to early stages of cellular HIV infection identified

August 8, 2017
When a virus enters a cell, one of the first steps in the process of infecting that cell is removal of the protein coat that surrounds the virus's genetic material. The virus can then produce DNA from its own genes and insert ...

Researcher develops safer gene therapy

November 4, 2016
A Washington State University researcher has developed a way to reduce the development of cancer cells that are an infrequent but dangerous byproduct of gene therapy.

Heart toxin reveals new insights into HIV-1 integration in T cell genome

July 20, 2017
Human immunodeficiency virus (HIV)-1 may have evolved to integrate its genetic material into certain immune-cell-activating genes in humans, according to new research published in PLOS Pathogens.

Recommended for you

Genetic changes tied to rare brain bleeds in babies

December 18, 2018
(HealthDay)—Researchers say they've identified genetic mutations linked with a blood vessel defect that can lead to deadly brain bleeds in babies.

Get a warrant: Researchers demand better DNA protections

December 18, 2018
New laws are required to control access to medical genetic data by law enforcement agencies, an analysis by University of Queensland researchers has found.

How a single faulty gene can lead to lupus

December 18, 2018
A research team at the Academy of Immunology and Microbiology, within the Institute for Basic Science (IBS) & Pohang University of Science and Technology (POSTECH) in South Korea has discovered the role of a key gene involved ...

New genetic testing technology enhances precision of analysis of clinical biomarkers

December 18, 2018
Estonian scientists have announced the invention of a genetic testing technology to analyse the number of clinical biomarkers at the single-molecule level, which enhances the sensitivity of tests in precision medicine and ...

Injection improves vision in a form of childhood blindness

December 17, 2018
A new treatment for patients with a form of congenital retinal blindness has shown success in improving vision, according to results published today in Nature Medicine led by researchers at the Scheie Eye Institute in the ...

Geneticists make new discovery about how a baby's sex is determined

December 14, 2018
Medical researchers at Melbourne's Murdoch Children's Research Institute have made a new discovery about how a baby's sex is determined—it's not just about the X-Y chromosomes, but involves a 'regulator' that increases ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.