Ness Bermingham, Interim CEO of Liberate Bio (SOURCE: Liberate Bio)
Liberate Bio: Pushing into the Future of Therapeutic Vectors
By Mark Terry
February 23, 2023
Gene therapies, which are now a reality, have demonstrated the effectiveness of using viruses as vectors to transport therapeutics, such as genes, into the body. However, as vectors, viruses come with various limitations and problems.
The COVID-19 vaccines by Pfizer-BioNTech and Moderna showed that vaccines could be effectively delivered using lipid nanoparticles. Use of nanoparticles to deliver various payloads, such as genes, CRISPR-Cas9 therapeutics, mRNA, and nucleotides is exploding and promises to resolve many of the issues inherent with viral vectors while dramatically improving the deliverability of therapeutics.
Nessan Bermingham, interim CEO of Liberate Bio, took time to talk to BioBuzz about the company, what they’re doing with nanoparticles, and the field in general. The company was formed in 2022 by Bermingham of Khosla Ventures, and Michael Mitchell of the University of Pennsylvania.
“When we think about things like genome editing, delivery of payloads like antisense oligonucleotides, mRNA, base editing, in many instances we actually are limited by the tissues or the cell types,” Bermingham says. “We can deliver predominantly into the liver, into some areas of the CNS, and into the eye. But there is a whole host of diseases that these technologies are very much applicable to that reside outside of these two or three different organs.”
One of the key challenges is how to get the payload to the appropriate organ or tissues and have it function appropriately. In addition to the issue of targeting is that viral vectors trigger the immune system to respond to those viruses, so Bermingham notes that they tend to be a “one-and-done therapy” because the immune system will attack the viral vectors if they’re used on a patient again.
The lipid nanoparticles used in the COVID-19 mRNA vaccines were essentially minuscule balls of fat into which segments of mRNA coding for part of the SARS-CoV-2 virus could be inserted. In general, Bermingham describes nanoparticles as something like putting a drop of oil into water and seeing a sphere form.
“You can actually implant your nucleic acid into the middle of that sphere so that when you deliver it into the body, it goes to certain regions of the body. So Liberate Bio was founded to allow us to generate nanoparticles that let us deliver these payloads to different regions of the body outside of the liver,” Bermingham says.
Another company Bermingham helped found and led as president and CEO until December 2017 is Intellia Therapeutics. The company has successfully demonstrated the delivery of CRISPR-Cas9 within nanoparticles for the potential curative treatment of ATTR, an inherited genetic disorder.
Bermingham says, “A number of groups are basically trying to identify what the characteristics are that we can put into these lipid nanoparticles to allow us to deliver the payload to specific cell types. The analogy we use it we have a train on a track that can deliver something to one place, but it can’t veer off that train track. Now we’re trying to figure out how to put wheels on it so we can effectively drive around to different regions that we program into it.”
This can be done by modifications to the vehicle/vector itself. One way is by way of size, shape, overall structure, charge, and other elements. The other approach, Bermingham says, “is to effectively decorate the nanoparticle with sort of zip codes that send it to specific cell types. Both of these mechanisms are being tested right now where we’re adding specific components to it to allow delivery to very specific receptors on specific cell types, or by changing the characteristics of the actual vehicle itself so that it is taken up by specific cell types.”
The first approved gene therapy was Spark Therapeutics’ Luxturna (voretigene neparvovec) for an inherited retinal disease caused by mutations in both copies of the RPE65 gene. It’s no accident that the first approved gene therapy was for an eye disease. It uses an adeno-associated virus (AAV) as a vector to deliver copies of the RPE65 gene directly into the eye. Eye diseases are low-hanging fruit for gene therapies because they can be directly injected into the affected organ.
By avoiding dissemination to the liver, tissue exposure, toxicities and immune reactions are decreased. It also requires significantly lower doses.
Bermingham’s co-founder, Mike Mitchell, from the Department of Bioengineering at Penn, focuses his research on biomaterials for overcoming biological barriers to drug delivery. Bermingham says, “Mitchell is one of the few that has done a lot of work and published a lot in the space around varying the nanoparticles, modifying the lipids in the nanoparticles, and then the recipe to actually make the nanoparticles.”
But Liberate Bio isn’t just interested in designing and providing nanoparticles to other biopharma companies, although that is a big part of their business model.
“The business model is actually twofold,” Bermingham says. “We identify novel delivery vehicles — we’ll partner with other companies that need them for their respective technologies, and second, build our own pipeline where we’re utilizing them for various modalities, all nucleic acid-based, for our therapeutic areas of interest.”
Those areas of interest typically are outside of the liver, like CNS disorders such as Huntington’s disease, and into the lung, for diseases like cystic fibrosis and others.
Noting that the field has come a long way and has great tools, capabilities, and the ability to quickly move into the clinic, there are still challenges. The cost of gene therapies is extremely high. With viral vectors, viral size limits the size of the payload. Bermingham notes that if you then decided to try and split the payload into two packages, the price goes up dramatically and manufacturing becomes even more complicated than it already is.
Another factor is how to shut off the payload, Bermingham says. “If you’re delivering CRISPR-Cas9, for example, it can be expressed all the time, when what you really want is for it to be expressed for 12 or 24 hours. There are also limitations around integration, with only about 1% of the payload being integrated into the body with some very significant toxicity issues around it within certain patient populations that we’ve seen in clinical trials of late.”
Liberate Bio believes it will get to the point where it can generate a synthetic delivery system that doesn’t have those limitations, is scalable, and will be targeted to specific tissues. Bermingham notes, “The final piece we need to solve is to get it out of the liver. And there are ways to do that, which is what Liberate Bio is focused on.”
Bermingham adds, “We want to have a bespoke system where companies can come to us and say, ‘This is the payload and these are the cells we want to deliver to, this is the size of the payload and the sort of kinetics that we need to drive to for the drug we’re looking to deliver.’ And we’re actually able to generate that for you and give it to you.”
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Mark Terry is a freelance writer, editor, novelist and ghostwriter. He holds a degree in microbiology & public health and spent 18 years in infectious disease research and clinical and research genetics prior to his transition to a writing career. His areas of expertise include biotechnology, pharma, clinical diagnostics, and medical practice management. He has written literally thousands of articles, as well as market research reports, white papers, more than 20 books, and many other written materials. He currently lives in Michigan with his family.
