Collaboration Key To Going "Out On A Limb" For Nonviral mRNA Delivery
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
A few months ago, I had the honor of joining four RNA therapeutics executives on stage and moderating a panel discussion during the RNA workshop at the World Vaccine Congress. Together, Beam Therapeutics’ Gopi Shanker, Replicate Bioscience’s Andy Geall, Hopewell Therapeutics’ Kate Zhang, and Orbital Therapeutics’ Gilles Besin tackled the biggest biological and technical challenges their companies are confronting today — of which (no surprise) there are many.
As we all know well, our push towards mRNA-based therapeutics raises big scientific questions about how our products function in vivo and how we can use LNPs and/or alternative delivery mechanisms to achieve targeted delivery. I think we’d all agree that prioritizing R&D to garner more foundational information about our molecules and to create a more diverse delivery vehicle toolbox is desirable. But in a sparse and more competitive financial climate, it’s not always easy (or affordable) for biotechs in the rush to the clinic to prioritize such research/product diversification.
Given the nascence of our space and just how much we need to learn, it should come as no surprise that each expert emphasized the importance of collaboration and partnerships to advance the RNA space. Though we may automatically limit our definition of “partnership” to the CDMO-biotech relationship (which the panel discussed in part 1), I was also reminded of the important role that academia and delivery technology platform companies play in this scientifically nascent industry. In fact, as the members of this panel went on to emphasize, they see great — and in some cases untapped — opportunities for collaboration to better advance nonviral delivery of a wide variety of RNA therapeutics.
Advancing LNP Delivery
Here at Advancing RNA, I’ve written several of my own columns as well as published contributed articles explaining why the complexities of lipid nanoparticle development should not be underestimated. (Please refer to the end of the article for a list of some recent favorites.) Though the mRNA vaccine approvals regulatorily “derisked” (to some extent) LNP delivery, it should go without saying that three mRNA vaccine approvals do not a therapeutics industry make. Afterall, as Zhang reminded us, delivery needs are drastically different for therapeutics than for prophylactic and therapeutic vaccine companies.
When we talk about LNP delivery of mRNA therapeutics today, there are two equally critical areas that get most of our attention, the first being manufacturing and quality. In fact, Zhang reminds her formulation team regularly, “You’re not just formulation, you’re also manufacturing.” Most often, however, our delivery discussions (& woes & grievances) center around our hurdles in getting our cargos to target and express in a specific cell/cells. As we explore using LNPs to deliver mRNA with more advanced/next-gen mechanisms of action, like base or prime editing, we need to take the discussion a step beyond just cell-type specificity. Though getting our cargo to the right cell type is the first critical step, Shanker reminded us that each cell is its own kingdom, governed by its own unique biological mechanisms. In other words, upon entering that cell, our product becomes subject to each cell’s unique “subcellular dynamics”, adding even more nuance to our products’ durability, potency, and translatability (which, as we already know, can be strikingly different between preclinical and clinical models.)
“It’s still early days and we’re only just starting to see how differences in subcellular dynamics in different cell types and how these biological intricacies influence our products’ performance,” Shanker added.
Given the increasing complexity of our drug products and the cellular worlds into which we’re sending them, Zhang expressed her excitement about the collaboration she’s seeing taking place between biotechs and LNP platform companies. It’s these collaborations that she feels will be essential to helping the industry learn more about the prospects and gaps in targeted LNP therapeutics delivery.
“Working with cargo companies is the only way delivery companies will expand their libraries and understand how each lipid can serve as a powerful delivery foundation for different cargo,” she explained. “In fact, it’ll only be through partnerships between LNP companies and cargo companies that we will achieve the next generation of LNPs.”
“Delivery Agnostic”: Diversifying Our mRNA/RNA Delivery Toolbox
Thanks to our previous RNAi and mRNA regulatory successes with LNPs, most of the encoding RNA space has continued to gravitate toward LNP delivery. But as I and others have begun arguing, there’s a certain amount of risk in attaching all our hopes of mRNA therapeutics’ future success to LNP delivery alone. That’s why I was particularly excited to hear Besin emphasize the importance of being “delivery agnostic” today.
“I don’t think anybody can say ‘I have the RNA delivery vehicle’ because we are in a position where we need to look at everything,” Besin argued. “We cannot ignore anything.”
In fact, as he argued in a previous Advancing RNA article, there are a lot of benefits — both financial and scientific — to identifying the limits of a biotech’s knowledge/platforms and where partnerships can offer a competitive edge and fill in important knowledge and skill gaps.
For example, both he and Geall expressed the importance of partnerships with academia today, particularly in building the foundational knowledge we need around newer nonviral delivery options. Though alternative delivery methods, like virus-like particles and polymers, have lagged behind LNPs in terms of investment and development, both experts acknowledged early research has revealed intriguing data.
However, it should go without saying that forging early-stage research partnerships with academia is not for the faint of heart. As Geall acknowledged, though Replicate’s early research suggests polymer delivery may be less immunogenic compared to LNPs, investing in and continuing this research may feel like going out on a somewhat shaky (yet expensive) limb.
“There aren’t any candidates or programs out there ready to go,” he admitted. In turn, he and his colleagues at Replicate are branching out into academia, establishing partnerships to start building polymer libraries — the screening and optimization of which likely won’t yield fruit for another year or, more likely, two. But “Long-term, we think polymers have a great trajectory for the therapeutics space,” Geall concluded. “It just requires us to play the long game.”
Continue on to Part 3, sharing the panel’s insights on the biological/scientific challenges we face in achieving the translational efficiency we need for mRNA therapeutics.
Miss part 1? Check it out here: From “Up & Coming” to “Fully Formed”: Maturing Our mRNA Outsourcing Partnerships
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