portions of the viral genome that are lethal to the host cell ... host genome. However, Thye ... âIf the cell survives
REPRINT FROM JANUARY 16, 2017
EMERGING COMPANY PROFILE
SEEKING VIRAL STRONGHOLDS BY EMILY CUKIER-MEISNER, SENIOR WRITER
Agenovir Corp. is using CRISPR-based gene editing to eliminate latent viruses. Its lead program will test in vivo delivery of CRISPR-Cas9 components to treat persistent human papillomavirus infection. Viruses that remain dormant within cells for years or decades after an acute infectious phase may recur or even drive pathologies while quiescent. Since they produce few proteins, they are nearly impossible to target and eradicate with conventional antiviral drugs or vaccines. Agenovir’s approach uses CRISPR constructs against viral DNA to destroy latent viral reservoirs. The constructs prevent viral replication and kill cells that harbor integrated viruses in their genomes. In a 2014 publication in Proceedings of the National Academy of Sciences, Agenovir co-founder Stephen Quake and colleagues reported designing CRISPR systems that suppressed viralinduced proliferation and restored apoptosis pathways in Burkitt lymphoma cells with latent Epstein-Barr virus (EBV) infection. They did so by employing multiple guide RNAs (gRNAs) targeting repeat regions of the virus. Quake is a professor of bioengineering and applied physics at Stanford University. President and CEO Dirk Thye said Agenovir’s tool kit includes CRISPR nuclease constructs that are optimized for potency and target selectivity using in silico design and simulation combined with non-computational methods. The approach combines publicly available design tools like GUIDE-seq with internal biological screening models to create the gRNAs that guide the nucleases to their targets. “We have this entire algorithm of cascading steps where we try to locate the most conserved region of the viral DNA with guesstimates of where we’ll have the most potency and least off-target activity,” said Thye. Director of Research Derek Sloan said Agenovir finds portions of the viral genome that are lethal to the host cell when disrupted, even if the virus is not integrated into the host genome.
AGENOVIR CORP. South San Francisco, Calif. Technology: Using CRISPR-Cas9 gene editing to eliminate latent viral reservoirs Disease focus: Infectious Clinical status: Preclinical Founded: 2014 by Stephen Quake, Angela Wu and Jianbin Wang University collaborators: Stanford University Corporate partners: None Number of employees: 12 Funds raised: $10.5 million Investors: Data Collective, Celgene Corp., Lightspeed Venture Partners, Stephen Quake, Peter Kim CEO: Dirk Thye Patents: 1 issued covering guided nuclease methods to treat viral infections
However, Thye noted that Agenovir’s programs can eradicate latent virus whether or not the host cell survives. “If the cell survives and is HPV-free, good. But in general the cell is a bad actor and we’re trying to kill it,” said Thye. Sloan added that the safety risk of off-target editing is low because Agenovir has unpublished data showing its products do not detectably cleave human genomic DNA at therapeutically relevant concentrations. Agenovir is initially targeting cancers associated with latent HPV infection — such as cervical or anal cancer — that could be treated with topical formulations. Doing so could make in vivo delivery easier and reduce the odds of systemic toxicity due to off-target editing. Sloan noted that poor uptake of prophylactic HPV vaccines means HPV is likely to persist in the population, and current treatment of HPV infection requires waiting for precancerous lesions to form so they can be removed surgically.
Thye said the tests can detect changes in persistent viral reservoirs, and that cervical cancer screening guidelines recommend HPV DNA testing every 3-5 years, depending on the woman’s age and advisory group. He did not answer questions about how often the recommended screening is performed. “Clinicians have told us they would much prefer to treat it at an earlier stage and prevent high-grade lesions from forming, but they don’t have another approach,” he said. Thye declined to say whether Agenovir will use viral vectors, lipid nanoparticles or other methods to deliver the CRISPR nucleases and gRNAs in vivo, and said that the company is still working on the formulation. Behind HPV, the company has programs targeting latent EBV and cytomegalovirus (CMV) infection. At least one other company, Excision BioTherapeutics Inc., is also using CRISPR to eliminate viral reservoirs. Its lead product, EBT101, is a CRISPRCas9/gRNA multiplex biologic in preclinical testing for eradication of latent HIV. Thye said Agenovir chose not to target HIV with its therapies because of the complexity of the HIV virus and because of Excision’s competing IP in the space. He was not aware of another company using CRISPR to
target the same viruses as Agenovir that has disclosed enough detail to compare the platforms. “We feel like we have identified a small niche within the CRISPR universe and that we have a pretty solid patent estate within that small niche,” said Thye. The company’s IP, which is exclusively licensed from Stanford under undisclosed terms, covers composition of matter, delivery technologies and specific targets related to CRISPR nuclease products for therapeutic treatment of latent viral infection. Thye said Agenovir plans to raise an undisclosed amount in a series B midyear. COMPANIES AND INSTITUTIONS MENTIONED Agenovir Corp., South San Francisco, Calif. Excision BioTherapeutics Inc., Philadelphia, Pa. Stanford University, Stanford, Calif.
REFERENCES Koch, S. “Shrinking reservoirs.” BioCentury Innovations (2016) Wang, J. and Quake, S. “RNA-guided endonuclease provides a therapeutic strategy to cure latent herpesviridae infection.” Proceedings of the National Academy of Sciences (2014)
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