On the road toward solving the PCO challenge

Take-home message: Targeting of Myo/Nog cells using a novel nanocarrier complex loaded with doxorubicin is showing promise as a treatment for reducing posterior capsule opacification.

By Cheryl Guttman Krader; Reviewed by Mindy George-Weinstein, PhD, and Liliana Werner, MD, PhD

Finding an effective strategy for reducing posterior capsule opacification (PCO)-the most common cause of vision loss after cataract surgery-continues to elude clinicians.

However, a novel platform providing targeted delivery of a cytotoxic drug to the cells that mediate this complication is showing promise.

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Intended for intraoperative administration, the targeted therapeutic product (G8-3DNA-Dox) achieves immunodepletion of Myo/Nog cells that are implicated in the development of PCO.

The drug is being developed by scientists at Genisphere LLC, Hatfield, PA, in collaboration with Mindy George-Weinstein, PhD, Cooper Medical School of Rowan University, Camden, NJ, and uses the company’s proprietary customizable 3DNA nanotechnology drug delivery platform.

The DNA nanocarrier can link together two different molecules-most often a drug and a targeting molecule. In G8-3DNA-Dox, 3DNA is intercalated with doxorubicin and complexed with a monoclonal antibody, designated as G8, which specifically targets Myo/Nog cells. Compared with a platform that only conjugates drug and antibody, the 3DNA nanotechnology can deliver a 100-fold greater load of drug to its target.

G8-3DNA-Dox specifically depletes Myo/Nog cells through induction of apoptosis without off-target effects.

The drug is currently being tested in the rabbit lens that aggressively develops PCO within 4 weeks of cataract surgery. The rabbit studies are being conducted under the direction of Liliana Werner, MD, PhD, and Nick Mamalis, MD, at the Intermountain Ocular Research Center, University of Utah, Salt Lake City.

Numerous advancements have been made to surgical techniques and IOLs in an attempt to reduce PCO, noted Dr. Werner, associate professor of ophthalmology, and co-director of the Intermountain Ocular Research Center.

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These changes include polishing the capsule to remove residual lens epithelial cells, as well as modifications in IOL design, she noted.

Different pharmacologic approaches have also been tried to prevent this problem.

Next: Addressing etiology of the problem

“Despite all of these attempts, PCO continues to be a significant postoperative complication, with a 3-year incidence that can be as high as 40%, and even higher in the pediatric population,” Dr. Werner said.

“The preventative treatment of PCO developed by Genisphere is very innovative in that it uses nanotechnology for drug delivery, which can be applied intraocularly during a standard cataract surgery procedure with IOL implantation,” Dr. Werner added. “While preliminary, the initial efficacy and safety results from the in vivo evaluation of G8-3DNA-Dox in the rabbit model are very promising.”

Addressing etiology of problem

“We are very excited about this approach to preventing PCO that addresses the etiology of the problem,” said Robert Getts, PhD, vice president, research and development, and chief science officer, Genisphere. “The 3DNA nanostructures are composed entirely of DNA and maintain the biocompatibility of the nucleic acid building blocks.

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“We are working now to optimize the formulation of G8-3DNA-Dox in order to maximize its efficacy, and we also need to complete preclinical safety studies,” Dr. Getts said. “Then we hope to obtain FDA approval to proceed into a clinical trial.”

Myo/Nog cells were discovered and characterized in the laboratory of Dr. George-Weinstein in collaboration with Jacquelyn Gerhart, MS, senior cell biologist, Genisphere. The team also generated the G8 antibody.

Dr. George-Weinstein and Gerhart showed that the Myo/Nog cells are present in the anterior and equatorial regions of the human lens, cornea, and ciliary body. Their studies with explants of human lens tissue demonstrated the Myo/Nog cells develop into myofibroblasts that synthesize skeletal muscle proteins.

Next: Work in progress

“We found that the Myo/Nog cells develop into myofibroblasts in response to injury, migrate onto the posterior capsule, and appear to contract to produce wrinkles,” Gerhart said. “These events are recapitulated during development of PCO which can be accompanied by capsular wrinkles that affect visual acuity.”

Work in progress

The ultimate goal is to develop a treatment that would be administered one time at the end of surgery, Dr. Getts noted. With that in mind, work encapsulating G8-3DNA-Dox into a sustained-delivery formulation is under development.

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“Using a sustained-delivery approach, we can achieve immediate and longer-term release to eliminate Myo/Nog cells that are present intraoperatively and also those that may appear later in response to wounding,” Dr. Getts said. “We are now continuing with research to fully understand the timing of Myo/Nog cell migration and to optimize the formulation that will maximize the duration of drug delivery.”

The investigators are also refining the drug formulation that will optimize delivery from the IOL.

Dr. George-Weinstein reflected on their work and long-standing collaboration with Dr. Getts.

“We began our research with the discovery of Myo/Nog cells in early chick embryo, followed their migration into the developing eyes and demonstrated that depleting them results in malformations of the lens and retina,” Dr. George-Weinstein said. “It is extremely rewarding to have years of our work culminate in an approach that may prove therapeutic to millions of individuals that undergo cataract surgery.”

Mindy George-Weinstein, PhD

E: george-weinstein@rowan.edu

This article was adapted from a poster presentation at the 2015 meeting of the Association for Research in Vision and Ophthalmology. Dr. George-Weinstein, along with Genisphere’s Robert Getts, PhD, and Jackie Gerhart, MS, are inventors on the patent that covers the use of 3DNA in treating posterior capsule opacification.

Liliana Werner, MD, PhD

E: liliana.werner@hsc.utah.edu

Dr. Werner’s laboratory performs contract research studies with Genisphere. She has no other financial interest to disclose.