Taking advantage of the viral world’s expertise in manipulating life is opening new doors for the biotech industry. Once only seen as our enemies, viruses are fast becoming some of our most valuable allies.
Viruses may not have the best public image, but to biotechnologists, there’s a lot to admire about them. These tiny molecular machines have unparalleled abilities, honed over billions of years of evolution, to infiltrate and exploit living systems — including ourselves.
Domesticating viruses has been an ongoing scientific endeavor for decades. Their talents as cellular hijackers make them extremely valuable as tools for a wide variety of biotech applications, from delivering gene therapies to killing superbugs. I caught up with several companies working on harnessing viruses to solve some of the biotech industry’s biggest challenges.
The threat of antimicrobial resistance was labeled “as big a danger to humanity as climate change or warfare” by the UK’s Health Secretary at the World Economic Forum earlier this year. Indeed, antibiotic-resistant infections are on track to kill 10 million people a year by 2050.
As the number of effective antibiotics in our arsenal continues to dwindle, the concept of tackling superbugs via bacteriophage viruses, natural predators of bacteria, has gained increasing interest around the world. These viruses have been killing bacteria for billions of years, and they’ve become very, very good at it.
‘Phages’ latch on to their bacterial target and hijack the cell’s internal machinery, forcing it to produce more viruses, which then burst out from within the bacterium, destroying it. And conveniently, they’re unable to infect human cells, so they are completely harmless to any patients being treated using phage-based therapy.
Vienna-based PhagoMed is pioneering the development of treatments for bacterial infections, with several phage-based candidates currently at the preclinical stage.
“Phages are able to kill bacteria irrespective of antibiotic resistance. They have a unique mode of action that can become a much-needed complement to the existing — and increasingly failing — antibiotics therapy,” Lorenzo Corsini, joint CEO and co-founder of PhagoMed, told me.
Phages also have the added benefit of being extremely precise in which bacterial strains they target. This prevents them from killing beneficial bacteria, which is a common problem with conventional antibiotics.
Of course, there’s still the question of whether bacteria could, in time, evolve resistance to phages as they have to antibiotics. However, Corsini believes that the emergence of resistance would be much easier to deal with.
“Eventually, it is possible that individual phages in a [treatment] will have to be replaced. The good news is that by becoming resistant to one phage, bacteria often become susceptible to another phage, so that there is a virtually infinite supply. Phages and bacteria have co-evolved for billions of years, and neither has managed to ‘win’ this evolutionary race.”
In the search for ever more precise and effective cancer treatments, the development of viruses that selectively destroy tumors is a rapidly growing field. Viruses are naturally adept at seeking out and infecting specific cells, making them ideal for targeting tumors with a high level of accuracy while leaving healthy cells undisturbed.
To date, only one oncolytic virus has been approved for use in the EU and US, Amgen’s T-VEC, a genetically engineered herpes virus for treating melanoma. However, there are many more at various stages of preclinical and clinical development and there’s been a wave of investment from big pharma giants over the last few years.
In Germany, Oryx Translational Medicine is working to develop the smallest of all oncolytic viruses, a virus that infects rats in the wild called ParvOryx. ParvOryx can selectively kill tumor cells from a wide variety of cancers including glioblastoma and pancreatic cancer, and owing to its small size it is able to pass the blood-brain barrier that protects the brain.
“There was initial skepticism about oncolytic viruses in biotech and pharma,” Bernard Huber, CEO of Oryx told me. “The main challenge for the use of oncolytic viruses is their pathogenicity to humans. Unlike most other oncolytic viruses currently under investigation, ParvOryx is not pathogenic to humans and does not affect normal cells or tissues.”
Not only does the virus directly infect and kill tumor cells, it also profoundly alters the tumor’s microenvironment, making it more visible to the immune system and increasing its vulnerability to immuno-oncology approaches.
“ParvOryx has demonstrated an excellent safety profile both as monotherapy and as combination therapy with antibody-based therapeutics, checkpoint inhibitors or chemotherapy. Even in repeated boost applications, currently considered the most promising treatment approach, no safety issues were observed,” Huber explained.
Oryx has completed two phase I/IIa clinical trials in recurrent glioblastoma and metastatic pancreatic cancer, successfully showing objective tumor response and increased overall survival.
Delivering genetic material
Perhaps the most fundamental characteristic of viruses is their inability to self-replicate without a host. To reproduce, they must infect a host cell, inject their DNA, and commandeer the cell’s machinery for replication. Their mastery of efficiently introducing genetic material into complex cells — crucial for their proliferation in the wild — forms the basis of one of the hottest technologies in biotech right now: viral vectors.
Viral vectors are essentially modified viruses that have had the pathogenic components of their genome removed, while retaining their skills as gene delivery vehicles. This makes them incredibly versatile tools for emerging technologies and treatments, most notably gene therapies, which rely on introducing genetic material into patients’ cells.
“Viruses have gone through eons of natural selection to make them the most advanced gene delivery tool imaginable, for any and all kinds of tissue and cell types,” said Christian Thirion, founder and CTO of Sirion Biotech, a German company developing viral vectors.
A recent example of a breakthrough gene therapy reliant on viral vectors is Luxturna, recently approved in the EU. Luxturna is able to restore sight in patients suffering from progressive vision loss due to a specific genetic mutation in the RPE65 gene, who had previously had no treatment options. Luxturna uses a viral vector to deliver a functional copy of the gene into retinal cells, restoring the patient’s vision.
There are several types of viral vectors derived from different classes of viruses, including lentiviral vectors based on the HIV virus, adenoviral vectors from common cold viruses, and adeno-associated viral vectors (AAVs) — the ones used in Luxturna.
“AAVs are the new superstars in the gene therapy sector,” said Thirion. “Wild-type AAVs don’t elicit disease in humans and result in long-term gene expression for up to 10 years. AAV capsids can be engineered and targeted towards specific cell or tissue types. All these features make them ideal tools for modern gene therapy applications, and the rise in interest in this technology has been steep.”
The surge in demand for viral vectors has triggered an industry-wide shortage over the last year. In response, Sirion has greatly expanded its manufacturing capabilities, joining a growing list of European viral vector players who’ve recently announced similar plans to scale up production capacity, including Oxford Biomedica, Vibalogics, and Cevec.
While their sinister reputation may never be fully erased, it’s clear that the more we study viruses, the more impressive they become and the more possibilities they offer us. Far from only being bringers of death and disease, viruses are rapidly establishing themselves as crucial enablers of powerful new treatments that would have been impossible without their help.
Farhan Mitha is a science communicator based in the UK, with a background in biology and science policy. When he’s not writing about science he’s performing stand-up comedy and then complaining about the gig minutes later on his twitter account @FarhanMitha.
Images via PhagoMed Biopharma GmbH, Sirion Biotech GmbH and Shutterstock.