Is The mRNA Payload The Real MVP of Targeted Delivery?
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
When we talk about targeted delivery in the RNA space, we naturally place a lot — if not all — of the emphasis on the LNP. In the Advancing RNA community alone, I’ve already hosted two Advancing RNA Live panel discussions (1 & 2), and I’ve penned a handful of articles focusing on the work being done on LNPs and/or other carriers to improve targeted delivery. (For starters, check out here, here, and here.)
However, as the following (delightfully colorful) quote from a panel discussion at the AMM Ascent meeting last fall reminds us, there’s a lot more to be explored, discussed, and understood as it relates to the mRNA cargo’s role in targeted delivery.
“In the most unsexy way I can paint it, mRNA is a protein delivery system…What I actually give a shit about is the protein that’s being produced... I could spend less time trying to get more mRNA over to the tissue of interest and less mRNA over to non-target tissues if I could control the translation event.” ~ Jake Becraft, CEO, Strand Therapeutics
Of course, there are numerous factors that contribute to a successful and well-controlled “translation event. Right off the bat, you already probably guessed that one of those factors is the quality of the mRNA. As an industry, we’re laser focused on improving and understanding the quality of our mRNA. However, there’s still a lot of work to be done to standardize the quality of the mRNA we’re relying upon in the earliest stages of research.
As we were politely reminded by Becraft during the panel, working with mRNA preclinically and/or in academia is particularly challenging because the mRNA can be all over the quality spectrum. For example, mRNA from a commercial kit can perform drastically differently than that which a process development scientist produces in a lab. As Becraft warned, it’s not unusual to find that low quality mRNA (thanks to, for example, a poorly controlled IVT reaction and/or low-quality raw materials) can quite often contribute to/cause skewed and/or bad data and ultimately lead to “throwing a billion-dollar drug in the trash.”
“People make really shit quality mRNA in their labs — myself included,” Becraft added. “I think it would behoove us as an industry and within our industry/academic collaborations to bring quality control and general specifications around how we’re all making mRNA,” he added.
We also have a lot of big goals for improving our mRNA, saRNA, or circRNA drug substances — a particularly important one being augmenting their protein expression capabilities to provide a more potent and durable therapeutic effect. However, seeing as targeted delivery is the end goal for our mRNA-based therapeutics, it’s also important that this enhanced protein expression only happens in the target tissues. Though there is an increasing amount of discussion on how to make our LNPs smarter by relying on both passive and active delivery approaches, Becraft and the panel argued we need to be just as focused on “educating” our mRNA/RNA cargo to be smarter about where it expresses itself as we are in getting the delivery vehicle to the proper tissues.
For Strand Therapeutics, this has meant exploring how to silence off-target mRNA to protect off-target tissues. “Should our mRNA hit the liver, the spleen, or any other organs that are not the target, we want that mRNA to be completely silenced,” Becraft explained. In fact, Strand’s recently released research in rodents has demonstrated that, “When you are able to knock down the mRNA and silence it in those off-target tissues, you revert that tissue type back to a wild-type phenotype. The tissue looks highly similar if not identical to what that tissue was prior to being hit with an off-target mRNA.”
Zdravka Medarova of TransCode Therapeutics also reinforced Becraft’s argument that focusing our efforts on tissue-specific release of payloads will be a much more valuable approach given a few basic truths. For one, as she explained, it’s going to be next to impossible to truly avoid the liver. In fact, seeing as the liver is our body’s tool for clearing drugs from our system, we don’t exactly want to avoid the liver entirely. Secondly, she was honest in admitting that she’s almost gotten into multiple “fist fights” over the use of targeting moieties. “They are not going to change things dramatically,” she clarified. Rather, she argued in favor of looking beyond antigen targeting to enhance tissue specificity.
“One way you could explore tissue-specific release is by making the mRNA silent by coupling it with a carrier so that it cannot enter the ribosome unless it comes off of the carrier,” she said. “The way it could be coupled to this carrier, for example, could be dependent on the expression of specific enzymes that are enriched in the specific cellular environment” (e.g., the tumor microenvironment).
If you liked hearing from Medarova and Becraft, be sure to check out more of their perspectives in previous Advancing RNA editorials: