Gene therapy scientists have long dreamed of curing blindness. The first commercial gene therapy in the US, Luxturna, was approved by the US Food and Drug Administration in 2017 to partially restore sight in a rare form of inherited vision loss. Since then, old and new drug companies alike have spent hundreds of millions of dollars to develop gene therapies for other genetic forms of blindness. More than 70 clinical trials are either planned or underway to test these treatments in people.
But there are hundreds of different mutations linked to vision loss, and a universal cure for blindness remains distant. Now, a new start-up plans to disrupt the ocular gene therapy sector with a therapy that would work for many forms of vision loss, whether inherited or acquired during life.
The company, Vedere Bio II, launched with $77 million in series A financing to develop what it calls a “mutation agnostic optogenetics technology” to restore vision. As its name suggests, Vedere Bio II is a sequel to its predecessor company, Vedere Bio, which Novartis quietly acquired last year in a deal worth up to $280 million.
Both Vedere companies are pioneering optogenetic gene therapies. Much of the field of optogenetics is rooted in the work of Karl Deisseroth, a neuroscientist at Stanford University whose lab developed techniques for implanting light-sensitive algae proteins called channelrhodopsins into the brain cells of living animals to turn specific neurons on or off. Neuroscientists have used the method to study the brain and create models of human diseases, and a few firms are even testing channelrhodopsin-based gene therapies in humans as a treatment for vision loss.
Vedere is taking a slightly different approach, based largely on the work of University of California, Berkeley, neuroscientists Ehud Isacoff and John G. Flannery. Their strategy relies on light-sensitive ion channels or G-protein coupled receptors (GPCRs) from mammals, rather than algae. Experimental gene therapies based on these proteins have partially restored vision in blind mice and dogs.
Cyrus Mozayeni, who cofounded the start-up as an entrepreneur-in-residence at the life science–focused venture capital firm Atlas Venture, says Vedere raised $21 million in series A financing and was talking to multiple firms about partnerships when Novartis offered to buy it last year.
“It was not our intent to sell that company,” Mozayeni says, and he wasn’t open to an offer unless he could spin off most of Vedere’s technology into a sequel start-up. When the deal closed in September 2020, Novartis ended up paying $150 million up-front to acquire Vedere’s lead candidates for vision restoration. Vedere could earn another $130 million in milestone payments.
When the acquisition was announced in October, it was the first that many people had heard of Vedere, which had been quietly operating at LabCentral, a biotech incubator in Cambridge, Massachusetts. By that point, Mozayeni was already at work on Vedere Bio II, which retained the original Vedere team and the intellectual property that wasn’t associated with the candidates that Novartis acquired. Funding for the sequel came even faster than the original. “It was kind of an amazing thing to see the level and intensity of interest in this space,” he says.
Mozayeni, who is now CEO of Vedere II, won’t disclose exactly how either Vedere I or II’s gene therapies work, but published research from Isacoff and Flannery offers some clues.
The photoreceptors in the human eye—rod cells for night vision and cone cells for color vision—both rely on GPCRs to kick-start the process of translating light into electrical signals that are transmitted to the visual centers of the brain. These GPCRs, known as rhodopsins in rods and opsins in cones, are themselves turned on by a small-molecule photoswitch. A bent form of that photoswitch, called 11-cis-retinal, absorbs a photon of light and straightens out into its trans-retinal form, activating the GPCR.
Many forms of inherited blindness are caused by genetic mutations that damage the photoreceptors. Interestingly, many of those mutations spare other cells involved in vision. In fact, photoreceptors don’t talk to the brain directly; their signal is passed to the so-called retinal ganglion cells, which themselves connect to the brain. In 2019, Isacoff and Flannery showed that they could insert opsin genes into the retinal ganglion cells of blind mice, thereby bypassing the broken photoreceptors, and partially restore vision.
Vedere Bio I was largely focused on opsin-based gene therapies reliant on 11-cis-retinal, Mozayeni says. Vedere Bio II is working on an improved system with a human GPCR that is slightly modified to covalently bind to a synthetic photoswitch similar to 11-cis-retinal. Mozayeni won’t name the GPCR or its photoswitch because the company is still “sorting out intellectual property filings.” But he does say that Vedere’s photoswitch could be key for treating some forms of vision loss caused by a defect in the chemical pathway responsible for making and recycling 11-cis-retinal.
As with many gene therapies, Vedere’s treatment will use adeno-associated viruses (AAVs) to carry the therapeutic gene into the body. While administering Luxturna requires surgery to inject the AAVs underneath the photoreceptors of the retina, Vedere’s therapy will be injected into the jelly-like vitreous humor of the eye. From there, it will deliver the GPCR gene to the retinal ganglion cells. The start-up has licensed AAVs from Berkeley that were optimized for intravitreal injection.
Vedere’s initial focus will be on treating retinitis pigmentosa, an inherited form of vision loss characterized by damaged or nonfunctioning photoreceptors. Other drug companies are developing gene therapies for specific forms of retinitis pigmentosa, which can be caused by mutations in more than 50 genes. Vedere’s approach is intended to work for any form of the disease, and the company will test the therapy in other inherited retinal diseases as well, Mozayeni says.
Vedere also intends to test its gene therapy in people with a form of vision loss that is increasingly common with age: geographic atrophy, an age-related macular degeneration (AMD) sometimes called dry AMD. Mozayeni concedes that Vedere’s approach won’t treat every form of vision loss, including optic nerve damage. But he thinks that the new firm can offer a treatment for the hundreds of thousands, if not millions, of people in the US with vision loss caused by damage to photoreceptors.
This story was updated on May 20, 2021, to correctly spell the name of one of Vedere Bio II's scientific founders. It is Ehud Isacoff, not Ehud Isachoff.
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