Gene Therapy in Ophthalmology Update 18: A RetroSense Update

I first learned about the potential of using gene therapies in treating ophthalmic disorders back in November 2010. That’s when I was introduced to gene therapy by Sean Ainsworth, the founder and CEO of RetroSense Therapeutics. I haven’t written about this company or the unique approach it is taking to try and treat retinitis pigmentosa and the dry form of AMD since that first article, The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD. With several news events occurring with the company recently, I felt it was time to bring readers of this blog up-to-date.

First, a brief review of the approach that RetroSense is taking. The technology that the company is using was developed at Wayne State University by Dr. Zhuo-Hua Pan. It involves using channelrhodopsin-2, delivered via an adeno-associated viral vector (AAV) directly into the retina to restore lost vision. Channelrhodopsin-2 is an “opsin”, derived from green algae which can be used to convert light-sensitive inner retinal neurons into photoreceptor cells, thereby imparting light sensitivity to retinas that lack photoreceptors. This is a process called “optogenetic therapy”.

As reported in Retina Today(1), “We took a new strategy for restoring vision by genetically converting the retina’s second- or third-order cells to become light sensitive to mimic the function of rods and cones,” wrote Dr. Pan. “But critical to this strategy, we needed to find certain suitable light sensors that can be easily inserted into these surviving retinal cells.”

Optogenetics is defined(2) as, “...the combination of genetic and optical methods to control specific events in targeted cells of living tissue, even within freely moving mammals and other animals, with the temporal precision (millisecond-timescale) needed to keep pace with functioning intact biological systems.”

           

In an interesting write-up about both optogenetics and RetroSense, Susan Young writing for MIT’s Technology Review(3), said, “The idea behind Retrosense's experimental therapy is to use optogenetics to treat patients who have lost their vision due to retinal degenerative diseases such as retinitis pigmentosa. Patients with retinitis pigmentosa experience progressive and irreversible vision loss because the rods and cones of their eyes die due to an inherited condition.”

She went on to say, “Retrosense is developing a treatment in which other cells in the retina could take the place of the rods and cones, cells which convert light into electrical signals. The company is targeting a group of neurons in the eye called ganglion cells. Normally, ganglion cells don't respond to light. Instead, they act as a conduit for electrical information sent from the retina's rods and cones. The ganglion cells then transmit visual information directly to the brain.”

“Doctors would inject a non-disease causing virus into a patient's eye. The virus would carry the genetic information needed to produce the light-sensitive channel proteins in the ganglion cells. Normally, rods, cones, and other cells translate light information into a code of neuron-firing patterns that is then transmitted via the ganglion cells into the brain. Since Retrosense's therapy would bypass that information processing, it may require the brain to learn how to interpret the signals.”

Before I relate the latest news about the company, I would like to share one further write-up about the company’s technology. This brief appeared in February, as part of an article in Popular Science entitled, “How Neuroscience Will Fight Five Age-Old Afflictions(4)”. One of the “afflictions” noted was blindness, and the writeup described RetroSenses’ approach to curing that affliction.

BLINDNESS

Gene therapy converts cells into photoreceptors, restoring eyesight

Millions of people lose their eyesight when disease damages the photoreceptor cells in their retinas. These cells, called rods and cones, play a pivotal role in vision: They convert incoming light into electrical impulses that the brain interprets as an image.

In recent years, a handful of companies have developed electrode-array implants that bypass the damaged cells. A microprocessor translates information from a video camera into electric pulses that stimulate the retina; as a result, blind subjects in clinical trials have been able to distinguish objects and even read very large type. But the implanted arrays have one big drawback: They stimulate only a small number of retinal cells—about 60 out of 100,000—which ultimately limits a person’s visual resolution.

A gene therapy being developed by Michigan-based RetroSense could replace thousands of damaged retinal cells. The company’s technology targets the layer of the retina containing ganglion cells. Normally, ganglion cells transmit the electric signal from the rods and cones to the brain. But RetroSense inserts a gene that makes the ganglion cells sensitive to light; they take over the job of the photoreceptors. So far, scientists have successfully tested the technology on rodents and monkeys. In rat studies, the gene therapy allowed the animals to see well enough to detect the edge of a platform as they neared it.

The company plans to launch the first clinical trial of the technology next year, with nine subjects blinded by a disease called retinitis pigmentosa. Unlike the surgeries to implant electrode arrays, the procedure to inject gene therapy will take just minutes and requires only local anesthesia. “The visual signal that comes from the ganglion cells may not be encoded in exactly the fashion that they’re used to,” says Peter Francis, chief medical officer of RetroSense. “But what is likely to happen is that their brain is going to adapt.”

Rewiring The Brain: Blindness: a) An eye diseased with retinitis pigmentosa has damaged photoreceptors, or rods and cones. Doctors inject the eye with a nonharmful virus containing the gene channelrhodopsin-2, or ChR2. b) The virus migrates into the retina at the back of the eye and inserts the gene into ganglion cells, which relay signals from the rods and cones to the optic nerve. The ganglion cells begin expressing the ChR2 protein in their membranes. c) Incoming light activates the ChR2 protein in ganglion cells, stimulating them to fire an electrical impulse. That message travels through the optic nerve to the brain’s visual cortex, which interprets it as a rough image.  Medi-Mation (Used courtesy of Popular Science)

What’s New

Within the past few weeks, the company has made two important announcements relative to its intellectual properties:

On March 5th, the company announced the notice of allowance for a new U.S. Patent Application broadly covering optogenetic approaches to vision restoration. The Patent Application broadly covers methods of restoring visual responses with a variety of optogenetic compounds. Specifically, the allowed application includes claims covering methods of restoring visual responses by delivering channelrhodopsin and variants thereof, as well as halorhodopsin to retinal neurons - with or without the use of cell-type specific promoters, including mGluR6 (Grm6). The subject opsins have been studied extensively and published on as means of vision restoration in retinal degenerative conditions such as retinitis pigmentosa and dry age-related macular degeneration.

The approved patent application is part of the "Pan" patent family, which stems from the novel research of Dr. Zhuo-Hua Pan and others at Wayne State University and Salus University, designed to restore vision in retinal degenerative conditions. Several Pan patent applications are part of RetroSense's intellectual property estate, which focuses on optogenetic gene therapies and complementary devices for vision restoration.

"We are pleased that the U.S. Patent Office has allowed this patent application, which will substantively expand the coverage of RetroSense's intellectual property estate. RetroSense continues to develop novel intellectual property in the area of optogenetics. Accordingly, we plan to continue to extend our basic patent protections on our technologies. We have also maintained an ongoing strategy to consolidate key intellectual property required to develop and commercialize optogenetics to restore visual responses," said Sean Ainsworth, Chief Executive Officer of RetroSense.

And, on March 27th, the company announced an exclusive option to intellectual property covering vision augmentation from Massachusetts General Hospital. This gives RetroSense the right to an exclusive, worldwide license to the patent application "Method for Augmenting Vision in Persons Suffering from Photoreceptor Cell Degeneration", based on the research of Dr. Richard Masland, director of the Cellular Neurobiology Laboratory in the MGH Department of Neurosurgery.

“This is an exciting development for RetroSense Therapeutics, as Dr. Masland’s work at Massachusetts General Hospital has been tremendous,” stated Sean Ainsworth, CEO of RetroSense Therapeutics. “This intellectual property broadens our reach and strengthens our existing position in optogenetic approaches to vision restoration.”

Dr. Masland stated, “The goal of the work we have done so far is to find a therapy that can help restore some level of vision to people who are now blind from retinal disease. I look forward to moving forward with this work.”

The next step for the company is to begin a Phase I human clinical trial. As noted in the Popular Science article, the company believes that is likely to occur sometime next year.

References:

1. Novel Optogenetic Therapy May Restore Vision After Retinal Degeneration, Callan Navitsky, Assoc. Editor, Retina Today, April 2012.

2.  From Wikipedia.

3 Company Aims to Cure Blindness with Optogenetics, Susan Young, MIT Technology Review, August 28, 2012..

4.  How Neuroscience Will Fight Five Age-Old Afflictions, Virginia Hughes, Popular Science, Feb. 18, 2013.