In major step toward the clinic, Ring’s human viral vector delivers gene therapy to eyes of mice

Ring Therapeutics’ hunt for new human viruses that can deliver gene therapies multiple times in a single patient appears to have landed on a viable candidate, new mouse data have suggested. 

In a preprint (PDF) posted March 30 to bioRxiv, a distribution service for research articles that have not yet been published, Ring scientists reported that a viral vector developed using the company's Anellogy platform, which is based on the human anellovirus, successfully delivered a gene to the retinas of mice. The company’s viral vectors, called Anellovectors, were expressed at stable levels for up to nine months without any signs of toxicity. 

“We set out to develop an entirely new vector system based on human commensal viruses to address the many hurdles facing current genetic medicine delivery—and we’ve achieved that at remarkable speed,” Ring CEO Tuyen Ong, M.D., said in a press release. “This new publication shows we can successfully harness the unique characteristics of anelloviruses to generate the Anellovector—the first novel viral vector in decades.” 

Preprint articles have not yet completed peer review, a process where scientists unaffiliated with the study take a critical eye to its methods and results before it’s officially accepted to an academic journal. While Fierce Biotech Research typically does not report on preprint studies, the announcement of a possible new candidate viral vector for gene therapy was significant enough to warrant coverage even at this stage. 

Nearly all the gene therapies approved by the FDA for treating genetic disorders arising from a single gene mutation—known as monogenetic disease—involve the use of adeno-associated virus vectors (AAVs). While reasonably safe and effective, as many as 70% of patients already have antibodies to AAVs, and those who don’t will likely develop antibodies to them after the initial dose. This means that AAV-based gene therapies can only be used once and must be administered in sufficiently high doses that the gene will be delivered to a sufficient number of cells to treat the condition. That can raise the risk of side effects. 

To get around those challenges, Ring is looking for new viruses that don’t raise the immune system’s alarm bells and could thus lay the groundwork for gene therapies that are dosed repeatedly. The company’s search is centered on anelloviruses, a family of viruses that aren't yet associated with any human disease and don’t appear to stimulate an immune response. In this case, the company tested a vector based on a virus from the Betatorquevirus genus. 

In the new study, Ring tested its Anellovector’s ability to deliver a gene expressing a fluorescent green protein to retinal cells. After seeing that it could do so in cell cultures, they tested it in live mice. The Anellovector delivered the gene to cells in the retina, where the researchers measured its expression at three, six and nine months. They found that while copies of the delivered DNA declined over time, the gene was expressed at stable levels from months three to nine. 

To see how its product stacked up against AAV vectors and whether they worked in tissue beyond the eye, the researchers injected either a dose of AAV9 vectors—one of the most commonly used AAV vectors—or its anellovirus vectors into the left and right ventricles of the brains of two separate groups of mice, where it expressed the same green fluorescent protein they had used to study their delivery efficacy in the retina. At 21 days post-injection, anellovirus vectors were at about the same levels as AAV9 vectors. Brain sections showed that expression levels were roughly the same between the two groups as well. 

“Taken together, these data demonstrate the Anellovector has tropism for cells in the CNS and suggests it can express its transgene to similar levels as an AAV9-based vector,” the researchers wrote in their study. 

Ring has also developed a production system for its Anellovectors. Called the Self-Amplifying Trans-complementation of a Universal Recombinant aNellovector (SATURN for short) system, it uses a self-replicating plasmid to package one anellovirus’ vector genome into the capsid of another. Experiments in the new study demonstrated that the SATURN system can do this between several different types of anellovirus species, which will potentially allow the company to make use of many different ones. 

Ring got its start at Flagship Pioneering, a Boston-based biotech incubator where Ong is also CEO-partner. The company has raised nearly $254 million so far, including a $117 million series B from in 2021 that attracted backing from the likes of Invus, Altitude Life Science Ventures and UPMC Enterprises in addition to Flagship. The biotech's most recent raise was a $86.5 million series C in March 2023. 

With the new preclinical results in hand, Ring is preparing to launch investigational new drug-enabling studies, Ong said in the release. The company's work hasn't been limited to mice, either. At the 2023 Annual Congress of the European Society of Gene & Cell Therapy last October, Ring shared that it had successfully used an Anellovector to deliver a gene to the retina in a pilot study involving nonhuman primates.