Before you read this blog, I wanted to share a photo that I took (yes with my iPhone 6…) last week of a beautiful sunset at Ocean Beach in San Francisco. I’m showing you this picture not to gloat that I live by the ocean, but to make a point. You’re able to enjoy this picture because you have the ability to see. But more than 20 million Americans in the US who suffer from some form of visual impairment can’t, and they are the inspiration for my blog today.
Age-related macular degeneration (AMD), the leading cause of blindness in the US, destroys the macula, the part of the eye responsible for central vision. Others patients suffer from retinitis pigmentosa (RP), which ravages the photoreceptors in the retina located in the back inside layer of the eye causing night blindness, tunnel vision, and eventually blindness. (For more on RP and AMD, check out our Stem Cells In Your Face video on “Eyeing Stem Cell Therapies for Vision Loss). Other diseases such as cataracts, glaucoma, and diabetic retinopathy can also cause people to lose some or all of their vision.
Unfortunately, there is no cure for many forms of blindness, but science has advanced to the point where multiple technologies are being tested in human clinical trials with the hopes of improving sight in blind patients. The two technologies I’m going to talk about today are optogenetics and stem cells – both innovative techniques that have made rapid progress in recent years.
What is optogenetics and how will it help restore sight?
First published about in the early 2000’s, optogenetics is a relatively new and really cool technology that can control how cells function by genetically manipulating them to be responsive to light. Scientists can use optogenetics to turn the activity of nerve cells in the brain on or off, to make muscle cells contract, and now to make eye cells activate in response to light.
The technique relies on light-sensitive proteins called opsins. Through genetic engineering, opsin proteins are delivered to the surface of the desired cell, and when they are exposed to the right wave-length of light, they send signals that turn the cells’ activity on or off.
Encouraged by the success of using optogenetics to restore sight in animal models of blindness, scientists are now hoping to test it in human clinical trials. A company called RetroSense Therapeutics in Ann Arbor, Michigan has developed a gene therapy technology that uses optogenetics, and it has partially restored sight in animal models. They’re targeting retinal ganglion cells, which are nerve cells located at the inner surface of the retina, and turning them into light-sensing cells to replace the ones that have died off.
A clinical trial using RetroSense’s optogenetics therapy is already underway in patients with RP and the trial’s first patient was treated at a clinic in Texas in February. The goal of the trial is baby steps – doctors hope that patients won’t experience negative side effects and that they will go from zero vision to some vision. You can read more about this clinical trial in a piece by Katherine Bourzac in the MIT Technology Review.
Stem Cell Treatments for Blindness in the Works
I’m switching gears now to talk about stem cell therapies for blindness. This area of research has received a lot more attention from scientists compared to optogenetics probably because it’s been around longer and offers more options for therapeutic development.
To be brief, scientists are testing the potential of stem cells to treat patients with diseases like RP and AMD using different types of stem cells including pluripotent stem cells (both embryonic and induced pluripotent or iPS) and retinal progenitor cells derived from fetal tissue. A common approach with AMD is to generate retinal pigment epithelial (RPE) cells – support cells that keep the retina healthy – from pluripotent stem cells and transplant them into the eye. Clinical trials around the world are testing the safety and efficacy of stem-cell derived RPE cells in patients with both the dry and wet forms of AMD.
In the US and Korea, Ocata Therapeutics (recently acquired by Astellas Therapeutics) generated RPE cells from human embryonic stem cells and transplanted them into patients with AMD in a Phase 1 clinical trial. They reported some improvement in vision and no adverse side effects and launched a Phase 2 trial in 2015. In Japan, scientists at RIKEN transplanted a living sheet of RPE cells from an AMD patient’s own iPS cells and transplanted them patients with AMD. While the first patient did not suffer any negative side effects, the trial was put on hold due to safety issues associated with findings from the iPS cells in laboratory tests. Other stem cell clinical trials are ongoing and you can read about them in this article in Drug Discovery & Development.
CIRM is also funding stem cell trials to treat blindness. One team led by Henry Klassen at UC Irvine, is using fetal retinal progenitor cells to treat patients with RP. They inject these cells into the fluid of the eye, and the cells release proteins and growth factors that boost the health of the remaining photoreceptors in the retina of RP patients. Another team at USC and UC Santa Barbara led by Mark Humayun, David Hinton and Dennis Clegg generated monolayer sheets of RPE cells derived from embryonic stem cells and growing them on synthetic scaffolds that will be transplanted into patients with AMD. Both teams are testing the safety and usefulness of their stem cell treatments in Phase 1 clinical trials. If you want to learn more about them, check out our recent blog.
So what will it be, optogenetics or stem cells?
It’s hard to tell which technology will be first to succeed in restoring sight to patients suffering from blindness and which technology will be more beneficial in the long run because both have their obstacles and vices.
Current optogenetics techniques require the use of viruses to transfer genes that contain the code for making the light-sensitive opsin proteins. These viruses are injected into the eye and have to target the right cells (and not the wrong ones) and the infected cell needs to produce that opsin forever for the technology to work effectively. Then there is the issue of making sure light can reach the genetically modified cells. Luckily nerves in the eye are easier to access than nerve cells in the brain, which require invasive surgery to implant optical fibers that deliver light. However, activating the ganglion nerve cells in the eye will still be a challenge according to MIT Technology review:
“Vision that works through light-sensitive ganglion cells will likely be different than vision that relies on a healthy retina. When you go outside, for instance, it can be about 10,000 times brighter than inside. Healthy retinas rapidly adapt their sensitivity to adjust to this, but the light-sensing cells created by the gene therapy will not likely be able to adapt. For that reason, it may be necessary for the RetroSense therapy, if it works, to be coupled with some kind of video-projection glasses that can perform these adjustments and tailor the incoming light to the treated eye, sending a brighter signal indoors than it does outdoors, for example.”
As for stem cells, there’s always the worry that transplanting cells derived from pluripotent stem cells could cause cancer over time. The Japan iPS cell trial for AMD is a good example. It was put on hold because scientists identified potential cancer-causing mutation in a second patient’s iPS cells. (The cause of the mutation was unknown – it could have been caused by the reprogramming method, the iPS cell culturing process, or could have existed prior to reprogramming). Another issue with stem cell treatments is achieving regulatory approval. In the US, the only widely stem cell based therapy is for bone marrow transplantation. If clinical trials using stem cells to treat diseases of blindness begin to show promising results, it would a major roadblock if they can’t push past current regulatory barriers and reach the patients who need them.
So which technology will cross the finish line first in the race to cure blindness: optogenetics or stem cells? The answer is that it doesn’t matter which technology wins. The important thing is they continue to move forward and hopefully one or even both technologies will produce a safe and effective treatment to restore sight in patients suffering from blindness in the near future.