This image from VectorBuilder showcases a comparative study of luciferase expression in various mouse organs, highlighting the targeted gene delivery capabilities of Anti-CD31 conjugated LNP-mRNA. Controls include IgG2a-conjugated FLuc LNP-mRNA and naked FLuc mRNA.
Genetic tools are growing more powerful by the day and hold immense medical promise. Kristofer Mussar, managing director of VectorBuilder GmbH who holds a Ph.D. in molecular genetics and epigenetics, noted that in the wake of the pandemic, genetic research requires increased awareness and ethical stewardship to responsibly tap into its power. While the current financial climate poses challenges, “the future is very bright in the cloning world and gene delivery,” Mussar noted. “At VectorBuilder, we’re all about innovation and having our finger on the pulse. We’re always focusing on the next thing.”
Earlier this year, VectorBuilder, which specializes in gene delivery technologies and offers an array of services ranging from vector design and cloning to gene therapy, reached a valuation surpassing $1 billion — unicorn status. The firm’s R&D projects run the gamut from exploring capsid evolution for novel capsids, a bacterial backbone-free plasmid, and antibody-conjugated lipid nanoparticles with mRNA. The company builds more than 80,000 vectors annually for tens of thousands of researchers globally, including prominent Big Pharma firms and research institutions, relying on its online vector design and ordering platform to streamline the complex process of vector cloning and virus packaging.
A pandemic claim to fame for VectorBuilder
Kristofer Mussar
During the pandemic, one of VectorBuilder’s claims to fame was pseudotyping the spike protein of SARS-CoV-2. “We modified our lentiviral vectors to make the coronavirus spike protein non-pathogenic and suitable for BSL-2 labs,” Mussar said. But while it was possible to work with the pseudotyped spike protein without extensive protective gear, it was “a headache and a half trying to ship those all around the world,” Mussar said.
Aiming to cure paralysis
The pandemic also highlighted the potential of mRNA in genetic medicine, a flurry of gene-centric research breakthroughs too often flies under the radar with significant potential. For instance, VectorBuilder has forged a partnership with South Korea–based Stand Up Therapeutics to develop an adeno-associated virus (AAV) to hopefully cure paralysis. “The PR and marketing opportunities for us are significant,” Mussar said. “If we can make people walk and stand up again, I believe everyone [who needs the therapy] should have access to it.”
Other advances include developments related to new viral vectors and editing techniques. “The big juggernauts are just picking and choosing and buying out the little companies to get, say, one piece of technology and paying sometimes billions just for a single vector,” Mussar said.
Reframing herpes in gene therapy
Some developments in the field may potentially raise eyebrows. Herpes simplex virus (HSV) is “going to be the new vehicle that’s going to be used in gene therapy in the next couple of years,” Mussar noted. “It’s going to be horrible to communicate to the public because they’re going to hear ‘herpes,’ and they’re going to think, ‘No, I don’t want that.’” But what makes herpes powerful as a vehicle is it allows large payloads of DNA to be delivered. “By including regulatory regions, you could maybe guide your therapy a lot better,” Mussar said, referring to DNA sequences that control when and where genes are activated in the body.
Beyond advances with specific therapies, the broader landscape of gene therapy is undergoing rapid transformation, Mussar noted. “The future is pushing the boundaries and finding new vehicles and optimizing the existing viral vectors and plasmids to accommodate lower toxicity, you know, like lower side effects, everything like that.”
CRISPR as a stepping stone
Mussar also highlighted continued progress in CRISPR technology, a technique that allows researchers to tweak the DNA of animals, plants, and microorganisms with extremely high precision. Recently, the FDA approved the first CRISPR-based gene edited therapy for the U.S. market, a significant advance coming a decade after Emmanuelle Charpentier and Jennifer Doudna’s groundbreaking CRISPR research and three years following their Nobel Prize win. Mussar acknowledged he had initial concerns with CRISPR technology, particularly regarding off-target effects. He likened the cautious approach to CRISPR to the initial cautious surrounding laser eye surgery. “With laser eye surgery, I used to be hesitant, saying, ‘Oh, I don’t want to get that because what if I go blind in 20 years?’” he said. “But now, it’s been around for more than 20 years, so I could basically say, ‘I should probably get it.’ It’s the same with CRISPR.”
CRISPR is part of a continuum of gene editing technologies, preceded by innovations like zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs). Mussar anticipates that “there’s going to be new enzymes that we find and new technologies that are going to be better than CRISPR over the next 10 to 20 years.”
Navigating the CRISPR patent maze
Mussar points out that intellectual property disputes are a hurdle in the field, highlighting the ongoing ‘CRISPR battle’ over patents and licensing rights between the Broad Institute (Harvard and MIT) and the University of California (UC) as adding a layer of complexity to scientific research. “That’s one of the most notable battles in our industry,” Mussar said, referring to the long-standing patent dispute over the groundbreaking CRISPR-Cas9 gene-editing tool.
This dispute has been ongoing since 2016 and despite several rulings in favor of the Broad Institute, an influential player in using CRISPR-Cas9 for genome editing in human cells, it shows little sign of ending. The outcome of this patent row could mean millions of dollars in royalties for the victor, as CRISPR-based therapies make it to market. Mussar notes the struggle of determining “who am I paying royalties to?”
Filed Under: Cell & gene therapy, Neurological Disease
