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Translational research through teamwork

NEI program aims to accelerate new therapies for blinding diseases
January 8, 2014
Dr. Krzysztof Palczewski

Dr. Krzysztof Palczewski.
Credit: Case Western.

Imagine you are building a house. You would need a team of specialists, including an architect, a general contractor, carpenters, an electrician, a plumber and many others. Now picture yourself leading an effort to develop a new therapeutic drug or device. For that, you’d need a very different kind of specialized team.

The National Eye Institute (NEI), part of the National Institutes of Health, has a research program designed to support this team-based approach. NEI’s Translational Research Program (TRP) on Therapy for Visual Disorders provides a lead investigator with up to $1.75 million per year for up to five years in order to assemble a multidisciplinary team, and move—or translate—potential new therapies beyond the research lab and into clinical trials.

In addition to bringing together an expert research team, investigators can use funding from the TRP to recruit experts on navigating the drug and device approval process overseen by the Food and Drug Administration (FDA). They can also use TRP funds to seek help in patenting new therapies. These steps are no less essential than lab work for bringing new therapies to patients.

“The program enables investigators to assemble multidisciplinary teams that can tackle scientific, technical, and regulatory issues that are beyond the capabilities of any single research group,” said Neeraj Agarwal, Ph.D., who oversees programs in research training and workforce development at NEI. The TRP began in 2000, and has funded one or two projects each year since.

Eyeing new drugs for retinal diseases

Krzysztof Palczewski, Ph.D., professor and chair of the pharmacology department at Case Western Reserve University in Cleveland, received a grant (EY021126) through the TRP in 2010. His goal is to develop new drugs for diseases that damage the retina, the light-sensitive tissue at the back of the eye.

Vision begins with cells inside the retina called photoreceptors. Chemicals called retinoids, which are derived from vitamin A, play a key role inside these cells. One type of retinoid, when combined with a protein called opsin, acts as a light-sensitive switch, converting light into electrical signals that are ultimately sent from the photoreceptors to the brain.

This cross-section of the retina has been stained to reveal the two main types of photoreceptors: rods (in red) and cones (green). Credit: Dr. Krzysztof Palczewski, Case Western.
This cross-section of the retina has been stained to reveal the two main types of photoreceptors: rods (in red) and cones (green). Credit: Dr. Krzysztof Palczewski, Case Western.

Unfortunately, the supply of retinoids is limited and they need to be recycled. Moreover, the recycling process isn’t 100 percent efficient. Dr. Palczewski has found that it can lead to the formation of a toxic byproduct called all-trans-retinal (atRAL), which may contribute to some diseases of the retina, such as age-related macular degeneration (AMD) and Stargardt disease. AMD is a leading cause of vision loss among people age 50 and older. Stargardt disease is a rare genetic disease that begins in childhood but has some similarities to AMD.

Several years ago, Dr. Palczewski began thinking about the prospects of a drug to treat Stargardt and AMD by counteracting atRAL. He reasoned that such a drug would have to be precise in its effects—because a drug that interfered with other retinoids could interfere with healthy vision. In one approach, he’s investigating whether drugs that the FDA has already deemed safe for treating a variety of disorders can be repurposed to treat Stargardt disease and AMD. In ongoing experiments, he’s been testing these drugs in animal models of Stargardt disease. Because Stargardt is a faster-developing disease, it’s an easier first target than AMD, he said.

As a biochemist by training, Dr. Palczewski has ample expertise in drug chemistry. But to test potential drug treatments in animals, he needed help. He recruited experts on biological imaging; on techniques to monitor the health of cells in the retina; and on devices that can be used to release drugs slowly, for long-lasting effects.

“The TRP has allowed us to bring these people together with a common goal, and to push the boundaries beyond what our individual labs can do,” Dr. Palczewski said.

In December 2011, Dr. Palczewski and his team reported testing two dozen FDA-approved drugs in a mouse model of Stargardt disease. The drugs are a diverse group, except that they all share a small bit of chemical structure that the researchers predicted would interact with atRAL. Indeed, the researchers found that two of the drugs—an anti-seizure drug and an anti-inflammatory drug—reduced damage to the retina in mice with Stargardt disease.

The group has also investigated the role of G-protein-coupled receptors (GPCRs) in Stargardt disease. This diverse family of proteins includes rhodopsin and many other proteins found in the retina. The researchers discovered that some GPCRs amplify the toxic effect of atRAL and others suppress it. About one-third of all prescription drugs work by either activating or inhibiting GPCRs. In November 2013, Dr. Palczewski’s group reported that several such drugs are beneficial in mice with Stargardt disease. Dr. Palczewski has co-founded a company, Visum Therapeutics, to move forward with developing drugs for Stargardt disease, and to begin testing them in clinical trials.

Targeting drugs to the right place

Dr. Henry Edelhauser. Credit: Emory.

Henry Edelhauser, Ph.D., a professor of ophthalmology at Emory University in Atlanta, was funded by a TRP grant (EY017045) from 2006 to 2010. His project focused on developing new methods for delivering drugs to the retina and other tissues at the back of the eye. Most ophthalmic drugs are delivered in one of two ways: through eye drops or injections into the vitreous gel, a clear fluid that fills the eye. A problem with either method is that the drug can spread throughout the eye, limiting the amount that reaches the retina and potentially causing side effects in other tissues toward the front of the eye.

To develop an effective method for drugs to reach the back of the eye, “we needed to facilitate collaboration between delivery system researchers and clinical researchers,” he said. He assembled a team to investigate a wide variety of delivery tools. One part of the team—led by Mark Prausnitz, Ph.D., a professor of biomedical engineering at Georgia Institute of Technology—was tasked with developing very short, thin injection needles called microneedles.

In one approach, the team studied whether a drug injected into tissues surrounding the eye could passively spread into the back of the eye. They conducted a series of experiments on anesthetized animals, spritzing a fluorescent dye near the sclera (the eye’s outer white coating), and then tracking the dye’s movement. They found that after these injections, the dye did indeed enter the eye, but it moved slowly, taking days to spread across the eye’s internal rear surface. During one of these experiments, the injection needle slipped into the eye just between the sclera and the retina, called the suprachoroidal space. To everyone’s surprise, the dye spread throughout this space within seconds.

The microneedles developed by Dr. Edelhauser and colleagues are short enough to just enter the suprachoroidal space (pink) without penetrating the retina (yellow.) See the full video at Vimeo. Credit: Clearside Biomedical.

After more experiments to verify this finding, Dr. Edelhauser and his team poured their efforts into refining their microneedles and injection techniques in order to target drugs to the suprachoroidal space. With key input from Dr. Prausnitz at Georgia Tech, the team was able to patent their technology and form a company for further development and testing, called Clearside Biomedical.

“One real key to our progress so far is that we had the right advice to put the patents together, and that came from the TRP award,” Dr. Edelhauser said. “Most scientists don’t know how to write a patent. It’s a unique art.”

The first eye disease that Clearside Biomedical will target is non-infectious uveitis, an inflammatory disease that causes swelling and damage to the uvea, a tissue layer in the eye that includes the suprachoroidal space. In a small trial (NCT01789320) that began recruiting in May 2013, the company will test whether microneedle injection of the drug triamcinolone acetonide (Triesence) is safe and well-tolerated by patients. Injecting this drug into the vitreous gel is an FDA-approved treatment option for uveitis, but can increase the risk of glaucoma and cataract. A more focused injection to the back of the eye may reduce this risk, Dr. Edelhauser said.

More projects and opportunities to watch

The TRP supports several other ongoing projects. One project at the University of Pennsylvania focuses on developing gene therapy for retinitis pigmentosa, a genetic disease that causes vision loss during childhood. Another project at Columbia University is geared toward developing gene therapies or small molecules to treat a variety of disorders—including some forms of retinitis pigmentosa and Stargardt disease—that are caused by abnormalities in the ABCA4 gene, which helps support retinoid recycling inside photoreceptors.

Other projects focus on new treatments for neovascular AMD (also called wet AMD), which involves an overgrowth of blood vessels in the eye. Current drug treatments inhibit a protein involved in this process, but may also block the protein’s nourishing effects on normal blood vessels. Two separate groups, at Scripps Research Institute and the University of Wisconsin-Madison, are investigating small molecules that might act through alternative routes.

“The research community has been enthusiastic about this program,” Dr. Agarwal said. “Because many vision disorders are rare, large pharmaceutical companies generally are not motivated to invest in new therapies for them. Even for more common conditions like AMD and glaucoma, the pharmaceutical industry is wary of investing at the earliest, highest-risk stages of therapeutic development. The TRP helps fill this void,” he said.

The TRP is supported through an R24 grant mechanism, which is generally used to support projects where diverse expertise and resources are needed. In order to be successful, applicants to the program need to outline a clearly defined path toward bringing a new therapy into clinical trials, Dr. Agarwal said.

NEI has announced funding to support several more projects through the TRP in the next few years. There are rolling application deadlines each January from 2014 to 2016. For more information, interested researchers should read the full announcement in the NIH Guide.


Chen Y, et al. “Systems pharmacology identifies drug targets for Stargardt disease—associated retinal degeneration.” Journal of Clinical Investigation, November 2013, DOI: 10.1172/JCI69076. Chen et al Pubmed

Maeda A, et al. “Primary amines protect against retinal degeneration in mouse models of retinopathies.” Nature Chemical Biology, December 2011. DOI: 10.1038/nchembio.759. Maeda et al Pubmed

Patel SR, et al. “Suprachoroidal drug delivery to the back of the eye using hollow microneedles.” Pharmaceutical Research, published online September 21, 2010. DOI: 10.1007/s11095-010-0271-y. Patel et al Pubmed