A team of University of California, Berkeley, scientists in collaboration with researchers at the University of Munich and University of Washington in Seattle has discovered a chemical that temporarily restores some vision to blind mice, and is working on an improved compound that may someday allow people with degenerative blindness to see again.
The approach could eventually help those with retinitis pigmentosa, as well as age-related macular degeneration. In both diseases, rods and cones die, leaving the eye without functional photoreceptors.
The chemical, called AAQ, acts by making the remaining, normally “blind” cells in the retina sensitive to light, said lead researcher Richard Kramer, UC Berkeley professor of molecular and cell biology. AAQ is a photoswitch that binds to protein ion channels on the surface of retinal cells. When switched on by light, AAQ alters the flow of ions through the channels and activates these neurons much the way rods and cones are activated by light.
“This is similar to the way local anesthetics work: They embed themselves in ion channels and stick around for a long time, so that you stay numb for a long time,” Kramer said. “Our molecule is different in that it’s light sensitive, so you can turn it on and off and turn on or off neural activity.”
Because the chemical eventually wears off, it may offer a safer alternative to other experimental approaches for restoring sight, such as gene or stem cell therapies, which permanently change the retina. It is also less invasive than implanting light-sensitive chips in the eye.
“The advantage of this approach is that it is a simple chemical, which means that you can change the dosage, you can use it in combination with other therapies, or you can discontinue the therapy if you don’t like the results. As improved chemicals become available, you could offer them to patients. You can’t do that when you surgically implant a chip or after you genetically modify somebody,” Prof. Kramer said.
“This is a major advance in the field of vision restoration,” said co-author Russell Van Gelder, MD, an ophthalmologist and chair of the Department of Ophthalmology at the University of Washington, Seattle.
The blind mice in the experiment had genetic mutations that made their rods and cones die within months of birth and inactivated other photopigments in the eye. After injecting very small amounts of AAQ into the eyes of the blind mice, Prof. Kramer and his colleagues confirmed that they had restored light sensitivity because the mice’s pupils contracted in bright light, and the mice showed light avoidance, a typical rodent behavior impossible without the animals being able to see some light. Kramer is hoping to conduct more sophisticated vision tests in rodents injected with the next generation of the compound.
“The photoswitch approach offers real hope to patients with retinal degeneration,” Dr. Van Gelder said. “We still need to show that these compounds are safe and will work in people the way they work in mice, but these results demonstrate that this class of compound restores light sensitivity to retinas blind from genetic disease.”
The current technologies being evaluated for restoring sight to people whose rods and cones have died include injection of stem cells to regenerate the rods and cones; “optogenetics,” or gene therapy to insert a photoreceptor gene into blind neurons to make them sensitive to light; and installation of electronic prosthetic devices, such as a small light-sensitive retinal chip with electrodes that stimulate blind neurons. Several dozen people already have retinal implants and have had rudimentary, low vision restored, Dr. Kramer said.
Eight years ago, Prof. Kramer and Prof. Dirk Trauner, a former UC Berkeley chemist now at the University of Munich, and their colleagues developed an optogenetic technique to chemically alter potassium ion channels in blind neurons so that a photoswitch could latch on. Potassium channels normally open to turn a cell off, but with the attached photoswitch, they were opened when hit by ultraviolet light and closed when hit by green light, thereby activating and deactivating the neurons.
Subsequently, Prof. Trauner synthesized AAQ (acrylamide-azobenzene-quaternary ammonium), a photoswitch that attaches to potassium channels without the need to genetically modify the channel. Tests of this compound and the current study are reported in the
July 26 edition of the journal Neuron
New versions of AAQ now being tested are better, Prof. Kramer said. They activate neurons for days rather than hours using blue-green light of moderate intensity, and these photoswitches naturally deactivate in darkness, so that a second color of light is not needed to switch them off.
“This is what we are really excited about,” he said.
FDA Approval For Glaukos iStent Implant
Glaukos Corp. has received Food and Drug Administration approval for its iStent Trabecular Micro-Bypass, the first ab interno glaucoma implant to be approved in the United States. The iStent is indicated for use in conjunction with cataract surgery for the reduction of IOP in adult patients with mild to moderate open-angle glaucoma currently treated with ocular hypotensive medication.
“Glaukos is pleased to be a leader in an emerging new procedural class called Micro Invasive Glaucoma Surgery,” said Thomas W. Burns, president & CEO, director of Glaukos. “Over the last decade, we have developed a complete portfolio of glaucoma stents to treat open-angle glaucoma and to contribute substantially to this new class of surgery. We believe that the iStent micro-bypass offers a compelling new treatment option for glaucoma specialists and comprehensive ophthalmologists to advance glaucoma patient care.”
iStent is a 1-mm implant, comprising non-ferromagnetic titanium, that is the smallest medical device known to be implanted into the human body. The iStent device is implanted in conjunction with cataract surgery and placed ab interno into Schlemm’s canal using an inserter and intraoperative gonioscopy.
The iStent is designed to create a bypass through the trabecular meshwork to Schlemm’s canal to improve aqueous outflow through the natural, physiologic pathway.
The IDE pivotal study for iStent conducted by Glaukos was the first prospective, randomized U.S. IDE trial for a glaucoma device. The trial, conducted at 27 sites, enrolled 239 subjects with mild to moderate open-angle glaucoma and clinically significant cataract. Subjects were randomized 1:1 to either iStent in conjunction with cataract surgery, or cataract surgery alone. The results showed that 68 percent of subjects in the iStent treatment group (combined cataract and iStent implantation) met the primary endpoint of IOP ≤21 mmHg with no medications at 12 months, compared to 50 percent of subjects in the cataract surgery only group. The treatment difference in favor of the iStent group on the primary endpoint at 12 months was statistically (p=.004) and clinically significant. Similar results were obtained on the secondary endpoint of a ≥20-percent IOP reduction versus baseline at 12 months with 64 percent of the iStent group achieving this endpoint compared to 47 percent in the cataract only group (p=.01).
Because iStent is implanted ab interno, the procedure is conjunctiva-sparing and blebless and preserves future therapeutic and surgical options for glaucoma patients. Glaukos has enrolled more than 4,000 patients worldwide in clinical studies evaluating iStent devices in open-angle glaucoma.
The most common adverse events included early postoperative corneal edema (8 percent), BCVA loss of ≥one line at or after the three-month visit (7 percent), posterior capsular opacification (6 percent), stent obstruction (4 percent) early postoperative anterior chamber cells (3 percent), and early postop corneal abrasion (3 percent).
A Micro Option for Ocular Injection
Microneedles may soon
provide a better way to administer injections to treat diseases such as macular degeneration. For the first time, researchers from the Georgia Institute of Technology and Emory University have demonstrated that microneedles less than a millimeter in length can deliver drug molecules and particles to the eye in an animal model. The injection targeted the suprachoroidal space of the eye, which provides a natural passageway for drug injected across sclera to flow along the eye’s inner surface and subsequently into the back of the eye. The minimally invasive technique could represent a significant improvement over conventional methods that inject drugs into the center of the eye, or use eyedrops, which have limited effectiveness in treating many diseases. The study was reported in the
July issue of Investigative Ophthalmology & Visual Science
“This research could lead to a simple and safe procedure that offers doctors a better way to target drugs to specific locations in the eye,” said Samirkumar Patel, the paper’s first author and a postdoctoral researcher at Georgia Tech when the research was conducted. “The design and simplicity of the microneedle device may make it more likely to be used in the clinic as a way to administer drug formulations into the suprachoroidal space that surrounds the eye.”
Mr. Patel, now director of research for Clearside Biomedical, a startup company formed to commercialize the technology, said the study also showed that the suprachoroidal space could accommodate a variety of drugs and microparticles. That could open the door for the use of timed-release drugs that could reduce the need for frequent injections to treat chronic eye diseases.
The study showed that injections of fluids containing molecules and particles into the suprachoroidal space not only reach the targeted structures, but remain there for extended time periods. And equally important, the molecules and particles do not significantly reach the anterior chamber, where side effects from drugs can occur.
“The study showed that if we inject non-degradable particles into the suprachoroidal space and wait as long as two months, the particles remain,” said Mark Prausnitz, a Regents professor in Georgia Tech’s School of Chemical and Biomolecular Engineering. “That means there is no natural mechanism to remove the particles from the eye. Knowing this, we can design biodegradable particles with drugs encapsulated in them that can slowly release those drugs over a period of time that we could control.”
Henry Edelhauser, MD, a professor of ophthalmology at Emory School of Medicine, said new compounds that pharmaceutical companies are developing to treat eye diseases will be most effective if they can be delivered directly to the portion of the eye that requires treatment, such as the choroid and retina that this delivery method targets. “With this technique, we are keeping the drug right where it needs to be for most therapies of interest in the back of the eye,” he said.
The stainless steel microneedles used in the technique are less than a millimeter long. The researchers believe that they will cause less trauma to the eye than larger hypodermic needles, and reduce the risk of infection.
The compounds used in this study fluoresced inside the eye, showing that they had reached their targets, but the compounds were not drugs. The next step, says Dr. Edelhauser, will be to study how well the microneedle technique can get real drugs to the eye structures of interest. REVIEW