Biotech start-up Ring Therapeutics, founded by Flagship Pioneering in 2017, hopes to transform gene therapy by using a new class of vector — anelloviruses – a diverse family of harmless viruses present in the human body. Current gene therapies mostly use an adeno-associated virus (AAV) to carry genetic material into a cell – often a one-and-done strategy with effects that have the potential to diminish over time. AAV is non-integrating (meaning it does not integrate into the cells’ DNA) so every time the host cell divides, the genetic material delivered as the therapy is reduced by half – it also can trigger a mild immune response. With anellovirus-based therapy, however, a patient may receive additional doses without triggering an immune response.
Avak Kahvejian, Ring CEO and Flagship partner, explains the potential advantages of anelloviruses over AAV, “We’ve taken these commensal viruses that are harmless, they developed specific advantages in terms of tropism, redosability, potentially being more tolerable and potent and we’ve been able to generate a platform around that … you can have indications that address both greater tolerability, which is an issue within the gene therapy space, greater potency, the ability to address different indications that are not addressed because of lack of tropism. And then the final holy grail is to address the redosability piece.”
The Vast Human Virome
Anelloviruses populate the human blood virome just as varied bacteria make up the human microbiome. Knowledge about the viruses, however, has been limited. Ring Therapeutics recently published findings that describe the broad genetic diversity of anelloviruses carried by humans. The Ring researchers, with colleagues at Harvard Medical School, Scripps Research Translational Institute, and the Gothenburg Global Biodiversity Centre, used new gene-sequencing technology to study 128 blood samples taken from transfusion donors and recipients before and up to 260 days after transfusion. They also scanned blood and serum samples from the National Heart, Lung, and Blood Institute’s longitudinal Transfusion-Transmitted Viruses Study and used publicly available anellovirus sequences from the National Center for Biotechnology Information’s GenBank.
Researchers designed a targeted rolling-circle amplification method, Anelloscope™, to characterize unique anelloviruses. They were able to describe and track the array of unique anellovirus lineages from each participant and reported that they produced a dataset containing 2,101 anellovirus sequences in total for further downstream analysis, nearly tripling the number of known anellovirus sequences.
In a press release from the company, Nathan Yozwiak, Ph.D., senior author of the paper and Senior Director, Viral Genomics, states that “Each anellovirus sequence represents a distinct type of outer shell (capsid) that could potentially encase and deliver a therapeutic gene or nucleic acid, such as RNA, to the human body. The newfound diversity of anelloviruses means that there are thousands of potential vectors for delivering gene therapy payloads.”
The researchers acknowledge that creating anellovirus-based vectors could be complicated, as the virus family displays extensive recombination, an aspect that contributes to its great diversity.
Persistence Is Key
Examining how the transfusion recipients’ anellovirus genomes, or “anellomes” changed over the months of the study after receiving donor blood led to a critical finding. The researchers found that transfusions changed the recipients’ anellomes without affecting their health and that some individual anellomes persisted for several months. According to the study, the persistence of newly transmitted lineages via blood transfusion suggests that an intravenous therapeutic could be a potent vehicle for delivery.
Disrupting Gene Therapy
Based on this research, Ring developed Anellogy™, a novel platform to use Anellovectors™ (anellovirus-based vectors) for gene therapy, and touts their technology as the “first true disruption in the gene therapy space in more than 50 years.”
Combining its deeper knowledge of the diverse anellovirus landscape with this new technology, Ring is planning to develop a range of redosable vectors capable of targeting specific tissues. The company predicts it will have a library of Anellovectors for external and internal clinical programs that may focus on therapeutic areas including oncology, cardiology, ophthalmology, CNS, rare diseases, pulmonary and beyond.
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