Two researchers at Weill Cornell Medical College have deciphered a mouse’s retina’s neural code and coupled this information to a novel prosthetic device to restore sight to blind mice. The researchers say they have also cracked the code for a monkey retina—which is essentially identical to that of a human—and hope to quickly design and test a device that blind humans can use.

The breakthrough, reported in the Proceedings of the National Academy of Sciences, signals a remarkable advance in longstanding efforts to restore vision. Current prosthetics provide blind users with spots and edges of light to help them navigate. This novel device provides the code to restore normal vision. The code is so accurate that it can allow facial features to be discerned and allow animals to track moving images.

The lead researcher, Sheila Nirenberg, PhD, a computational neuroscientist at Weill Cornell, envisions a day when the blind can choose to wear a visor with a camera that will take in light and use a computer chip to turn it into a code that the brain can translate into an image.

“It’s an exciting time. We can make blind mouse retinas see, and we’re moving as fast as we can to do the same in humans,” says Dr. Nirenberg, a professor in the Department of Physiology and Biophysics and in the Institute for Computational Biomedicine at Weill Cornell. The study’s co-author is Chethan Pandarinath, PhD, who was a graduate student with Dr. Nirenberg and is currently a postdoctoral researcher at Stanford University. 

This new approach provides hope for the 25 million people worldwide who suffer from blindness due to diseases of the retina. Because drug therapies help only a small fraction of this population, prosthetic devices are their best option for future sight. “This is the first prosthetic that has the potential to provide normal or near-normal vision because it incorporates the code,” Dr. Nirenberg explains.

In normal vision, light falls on photoreceptors  and the retinal circuitry then processes the signals from the photoreceptors and converts them into a code of neural impulses. These impulses are then sent up to the brain by the retina’s output cells, called ganglion cells. The brain understands this code of neural pulses and can translate it into meaningful images. 

Blindness is often caused by diseases of the retina that kill the photoreceptors and destroy the associated circuitry, but typically, in these diseases, the ganglion cells are spared.

Current prosthetics generally work by driving these surviving cells. Electrodes are implanted into a blind patient’s eye, and they stimulate the ganglion cells with current. But this only produces rough visual fields.

Many groups are working to improve performance by placing more stimulators into the patient’s eye. The hope is that with more stimulators, more ganglion cells in the damaged tissue will be activated, and image quality will improve. 

Other research teams are testing use of light-sensitive proteins as an alternate way to stimulate the cells. These proteins are introduced into the retina by gene therapy. Once in the eye, they can target many ganglion cells at once.

But Dr. Nirenberg points out another critical factor: “Not only is it necessary to stimulate large numbers of cells, but they also have to be stimulated with the right code—the code the retina normally uses to communicate with the brain.” This is what the authors discovered, and what they incorporated into a novel prosthetic system.

Dr. Nirenberg reasoned that any pattern of light falling on to the retina had to be converted into a general code, a set of equations, that turns light patterns into patterns of electrical pulses. “People have been trying to find the code that does this for simple stimuli, but we knew it had to be generalizable, so that it could work for anything—faces, landscapes, anything that a person sees,” she says.

In a eureka moment, while working on the code for a different reason, Dr. Nirenberg realized that what she was doing could be directly applied to a prosthetic. She and her student, Dr. Pandarinath, immediately went to work on it. They implemented the mathematical equations on a “chip” and combined it with a mini-projector. The chip, which she calls the “encoder,” converts images that come into the eye into streams of electrical impulses, and the mini-projector then converts the electrical impulses into light impulses. These light pulses then drive the light-sensitive proteins, which have been put in the ganglion cells, to send the code on up to the brain. 

The entire approach was tested on the mouse. The researchers built two prosthetic systems, one with the code and one without. “Incorporating the code had a dramatic impact,” Dr. Nirenberg says. “It jumped the system’s performance up to near-normal levels; that is, there was enough information in the system’s output to reconstruct images of faces, animals—basically anything we attempted.”

In a rigorous series of experiments, the researchers found that the patterns produced by the blind retinas in mice closely matched those produced by normal mouse retinas.

“The reason this system works is twofold,” Dr. Nirenberg says. “The encoder is able to mimic retinal transformations for a broad range of stimuli, including natural scenes, and thus produce normal patterns of electrical pulses, and the stimulator (the light-sensitive protein) is able to send those pulses on up to the brain.”

“What these findings show is that the critical ingredients for building a highly-effective retinal prosthetic—the retina’s code and a high resolution stimulating method—are now, to a large extent, in place,” she says.

The retinal prosthetic will need to undergo human clinical trials, especially to test safety of the gene therapy component, which delivers the light-sensitive protein. But Dr. Nirenberg anticipates it will be safe since similar gene therapy vectors have been successfully tested for other retinal diseases. “This has all been thrilling,” she says. “I can’t wait to get started on bringing this approach to patients.”

Both Drs. Nirenberg and Pandarinath have a patent application for the prosthetic system filed through Cornell University.

Scientists at the Singapore Eye Research Institute and Nanyang Technological University have developed a new way to combat post-surgical scarring for glaucoma patients. Their new drug delivery method has resulted in 40 percent fewer injections needed by glaucoma patients to prevent scarring after surgery. This also means fewer hospital visits for these patients in the future.

Glaucoma affects about 3 percent of the population in Singapore and an estimated 30 percent of sufferers require surgery to adequately control the disease. 

However, success rates for glaucoma surgery in Asian patients are considerably lower than those reported in Caucasian patients because Asians have a higher risk of scarring after such surgery. Up to one in three operated patients requires a minor surgical procedure in the first six months in order to maintain the ideal low postoperative eye pressure.

“The postoperative scarring response is the major obstacle for successful glaucoma surgery. We’ve seen in our clinics that Asian patients scar earlier and more aggressively than their Caucasian counterparts, and a significant number require at least one postoperative intervention to treat this scarring response,” said Associate Professor Tina Wong, MBBS, FRCOphth, PhD, senior consultant with SNEC’s Glaucoma Service, and head of the Ocular Therapeutics and Drug Delivery Research Group at SERI. She is also the senior author of this study.

The breakthrough treatment method is made possible by Professor Subbu Venkatraman, acting chair of NTU’s School of Materials Science and Engineering, who invented a way to make the drug, which prevents post-surgical scarring, last longer at the site of the injection. This considerably increases the interval before the drug has to be administered again. 

Using a hyaluronic acid gel, Prof. Venkatraman discovered a way to contain 5-fluorouracil inside the gel. “Leveraging NTU’s expertise in controlled-release technology, we have found a way to deliver the drug 5-fluorouracil gradually into the patient,” said Prof. Venkatraman. “This allows the drug to be time-released over several days, compared to the current effect of the drug which remains at the injected site for only a few hours. The benefit for patients who have undergone glaucoma surgery is clear—fewer injections of the drug are needed. This results in less post-surgical scarring and fewer visits to the hospital.”

The clinical trial involved 49 patients who were randomized to receive an injection of either the current 5-fluorouracil solution or the new combined formulation following bleb needling. All subjects were followed for three months. The team found that the subjects who were randomized to receive the new treatment had an improved postoperative outcome. “With this novel treatment, we observed a dramatically lower rate for repeat needling, with only 12 percent requiring further intervention, whereas 50 percent of subjects receiving the standard 5-FU solution treatment required further needling,” said Dr. Arun Kumar Narayanaswamy, senior clinical research fellow at SERI, and first author of this study.

“In addition, because these patients require fewer interventions, their risk of ocular infection and side effects are significantly reduced,” he added.

Dr. Wong, also an adjunct professor at NTU’s School of Materials Science and Engineering, and Prof. Venkatraman, together with his team of scientists, are improving the new treatment method further using nano-encapsulation. The team aims to achieve a precise release of the correct amount of drug at a steady daily dose over a course of several weeks instead of just a few days as shown by the study.

“Because the acute and most active stage of wound healing occurs in the first 12 weeks after surgery, we ideally need a sustained time release of the anti-scarring drug that can be administered as a single injection and provide the right amount of drug to continually suppress the scarring response for that crucial time frame,” said Dr. Wong. “That way, we won’t have to keep injecting patients with top-ups, often on a fortnightly or even weekly basis, which is not only inconvenient for the patient but greatly increases the risk of complications with each additional injection.”

In the future, this novel treatment could also be applied at the time of the glaucoma surgery to further improve surgical outcomes, as well as reduce the possible need for or frequency of bleb needling interventions after surgery.

Data from two Phase III clinical trials evaluating ThromboGenics’ ocriplasmin for the treatment of vitreo-macular traction and macular holes were published in the New England Journal of Medicine on August 16, 2012. The paper reported that a single intravitreal injection of ocriplasmin resolved vitreomacular adhesion (VMA), releasing traction and closing macular holes in significantly more patients than placebo. VMA is also referred to as symptomatic vitreomacular adhesion.

The two multicenter, randomized, double-blind Phase III trials with ocriplasmin were conducted in the United States and Europe and involved 652 patients with VMA. Both studies met the primary endpoint of pharmacological resolution of VMA at day 28. Secondary endpoints included nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy and improvement in visual acuity.

The Phase III program found that 26.5 percent of patients treated with ocriplasmin saw resolution of VMA, compared with 10.1 percent of patients receiving placebo (p<0.001). Nonsurgical closure of macular holes occurred in 40.6 percent of ocriplasmin-treated patients, compared with 10.6 percent of patients on placebo (p<0.001). Patients given ocriplasmin were more likely to achieve a vision gain of at least three lines compared with placebo. Treatment with ocriplasmin was associated with some, mainly transient, ocular adverse events.

Julia Haller, MD, ophthalmologist-in-chief of the Wills Eye Institute, and professor and chair of the Department of Ophthalmology at Thomas Jefferson University, said, “This New England Journal of Medicine paper highlights data showing ocriplasmin’s potential to become the first pharmacological option for the treatment of symptomatic VMA and macular holes. An in-office injection would be a new and possibly earlier alternative treatment for the vitreoretinal surgeon to offer to patients with these sight-threatening disorders. Ocriplasmin represents a potential new treatment paradigm for the retina community and for our patients with VMA and macular holes.”

ThromboGenics has made regulatory filings for ocriplasmin in both the United States and Europe. Last month, an FDA advisory panel recommended the approval of ocriplasmin for the treatment of symptomatic VMA. If approved, the Company plans to commercialize ocriplasmin itself in the U.S. In Europe ocriplasmin is currently under regulatory review by the European Medicines Agency. In March 2012, ThromboGenics signed a strategic partnership with Alcon (Novartis) for the commercialization of ocriplasmin outside the United States.

Market research conducted by ThromboGenics suggests that there are approximately 500,000 patients in the United States and the major EU markets who could potentially benefit from ocriplasmin annually. If approved, ocriplasmin will be the first pharmacological treatment for symptomatic VMA.  REVIEW