Trillium Ag：Discussing the Challenges and Opportunities of RNAi Agtech and Unlocking RNAi to Empower A New Era of Crop Protection

″The key challenges are really the biggest opportunities for companies like Trillium Ag, in overcoming the many significant roadblocks to more effective and widespread use of RNAi in agriculture," stressed Todd Hauser, Co-Founder and CEO of Trillium Ag in a recent interview with AgroPages.

Todd also shared his views on the challenges and opportunities of the development, commercialization & application situation of RNAi agtech, Trillium’s special approaches to make RNAi more effective, product pipeline & commercialization strategy, and more.

Todd Hauser
Co-Founder and CEO of Trillium Ag

What is driving the development of RNAi agtech?

At a high level, the drivers of RNAi agtech are the same circumstances fueling growth of ag biologicals overall: the urgent need to satisfy global food demand in the face of increasing population growth and climate volatility, and the many economic, safety, and environmental issues hampering current farming methods. These are big and enduring challenges that RNAi has the potential to address in many ways.

Then, of course, there’s the diminishing efficacy of existing synthetic products, the need for farmers to grow their arsenal of integrated pest management solutions, and the regulatory demands on manufacturers for stacked modes of action in their products. RNAi agtech addresses each of these needs, as well.

More specifically, RNAi has several unique features which offer additional opportunities to farmers and suppliers compared to genome editing technologies such as CRISPR/Cas or TALENs. Exploiting and advancing these features will continue to drive the development of RNAi agtech companies and products.

What makes RNAi agtech special relative to conventional agrochemicals?

Beyond these broader market tailwinds, other key factors have bolstered RNAi’s rise to replace agrochemicals as the next phase of species-specific pest management. One is sustainability; as a natural biological, RNAi offers greater specificity and improved biosafety compared with chemical pesticides and some alternative biocontrol strategies.

Another is regulatory. While there is still a lot in flux around RNAi products as they come to market in different regions globally, existing PPP risk assessment approaches can be reliably used to evaluate RNAi products. RNAi plants are being assessed, approved, and regulated – primarily outside the EU – using existing regulatory frameworks for GMO.

What and where are the biggest opportunities for it?

RNAi has made the most early progress as a pesticide against western corn rootworm (WCR), although it’s taken a long time to get there. More broadly, the mechanisms of RNAi can and are being applied across plant protectant categories – insecticides, herbicides, fungicides – to help reduce the huge global crop production losses each year due to pests (up to 40%).

Invasive insects alone cost the global economy at least $70 billion annually, while plant diseases add over $220 billion to those losses. Add to that the savings and other gains from potential crop enhancement applications, and you get a sense of how significant and important the opportunities are for us, as well as growers, consumers, agtech firms, and our global population overall.

Could you describe the current development state of RNAi agtech, especially its commercialization & application situation?

Despite a rocky start for RNAi in agriculture, with a lot of money spent by Big Ag on technologies that either failed to deliver on its promise or lacked a strong IP foundation (or both), there are more RNAi agtech companies than ever operating in or entering the market, and more investor dollars flowing into this sub-sector.

Overall, it’s still very much in the early stages, with a very small number of products entering the market as they navigate both the technical and potential regulatory challenges involved. But the significant potential has made agtech a strong emergent sector for institutional investment. Corteva CEO, Chuck Magro, shared at the World Agri-Tech Summit earlier this year that he believes biologicals are the fastest growing sector in crop protection, and that biologicals, like RNAi agtech, will make up 25% of crop protection revenues by 2035.

This is driving major firms like BlackRock to establish sector funds and increasing overall global investments – and the overall pool of investors. The focus has been especially strong in the ag biotech sector that includes RNAi agtech. Even while funding for companies in the broader agfoodtech category dropped last year from its all-time high of $52B in 2021, investment in ag biotech actually increased during that same period by 8%, with biopesticide-related companies – including RNAi agtech – accounting for nearly 70% of those dollars.

What are the key challenges affecting its development and market growth?

The key challenges are really the biggest opportunities for companies like Trillium Ag, in overcoming the many significant roadblocks to more effective and widespread use of RNAi in agriculture.

While the mechanisms of RNAi can be quite potent and potentially ubiquitous across agricultural applications, today’s RNAi agtech uses double-stranded RNA (dsRNA) as the RNAi trigger – which itself failed to demonstrate commercialization readiness over the years. Ultimately, dsRNA has proven inactive for the majority of economically-valuable uses and has fallen short of its potential. And, for the handful of uses where there is activity, the dsRNA-based products suffered from acquired and cross-resistance. The problem with the commercialization of RNAi agriculture is that the technology lacks the ″bioavailability″ characteristics required for efficacious use. Bioavailability defined by multiple biophysical and biochemical features that impart open-field stability - particle size preferences, target cell receptor interactions, electrostatic charges and target cell entry, among others. Typical dsRNA is negatively charged and crosses membranes poorly; in pharma, you can get around this limitation with a synthetic chemical formulation that alters the surface properties of RNA, but in agriculture that’s not an option.

As a result, RNAi has remained a largely unrealized modality for agriculture. Less than a handful of commercial seed trait products have been released, and those are limited to one class of insects. This leaves over 90% of economically valuable crop pests with needs un-addressable by standard RNAi solutions today, critically across Hemiptera and Lepidoptera species.

How is Trillium Ag working to address those challenges?

We take several different approaches to make RNAi more effective in agriculture. This starts with the RNAi trigger, which has been re-invented in the form of a novel single-stranded, multivalent RNA molecule (″MV-RNA″) that itself has key advantages over dsRNA. From there, we engineered a novel RNA-based scaffold to maintain an ideal particle diameter for bioavailabilty, and then we added first-of-its-kind self-formulation features to the RNA that precisely recruit specific proteins to form a shell-like surface over the RNA, ultimately reprogramming the ″bioavailability″ profile to match the needs of the agricultural use.

This design allows us to build nearly unlimited compositions for improved reliability, durability, stability, targeting, and uptake. It also enables us to create these molecules – which we call ‘Agrisomes’ – with multiple MOAs within a single molecule, which dsRNA does not support.

All of which helps us mimic nature’s own mechanisms, like lipid and/or protein interactions for cell-to-cell transport, to overcome the critical roadblocks of acquired resistance, uptake, cell delivery, and other challenges which hamstring traditional approaches to RNAi agtech.

This stable design also makes Agrisomes viable as a seed trait or in topical/sprayable applications. Overall, our Agrisome solution is much more a scalable, flexible platform than a product, with tunable properties that enable design of new molecules with new MOAs and capabilities over time.

Could you describe your current product pipeline and commercialization strategy?

Our current R&D is focused on demonstrating how ‘Agrisome’ solves bioavailability barriers against not only coleoptera – specifically WCR, where we’ve already had strong success – but also in Hemiptera and Lepidoptera, the most valuable classes of crop pests. Which are also where previous RNAi agtech has failed.

Current and previous collaborations with Big Ag leaders have provided validation across many different aspects and applications – which continues to drive additional commercial collaboration opportunities with new and existing partners.

While we’re focused on these three RNAi bioinsecticide programs, we’re also doing limited trials of Agrisomes in bioherbicide and even bioaquacultrure applications. In these and other studies, we continue to see results hold significant promise for Agrisomes to reduce crop losses and increase yields as part of a sustainable IPM strategy.

All of this, along with our growing global patent portfolio, gives us a good deal of opportunity and flexibility when it comes to commercialization. We remain highly agile at this point in that regard.

Are there any other recent notable developments at Trillium Ag?

We were very excited to add two renowned industry leaders to our team recently. Earlier this year Dr. Neal Gutterson, former Corteva Agriscience CTO and a leading innovator and visionary in agricultural biotechnology, joined our Board of Directors. Dr. David Fischhoff, recognized globally as one of the founders of agricultural biotechnology, joined Trillium Ag in June to chair our Scientific Advisory Board. Dr. Fischhoff was a longtime biotechnology leader at Monsanto and spearheaded the discovery and original development of insect-resistant crops.

It's very notable, and very special to us, to have two top innovators coming out of Big Ag companies join together to work with our team. Their proven expertise and deep industry insights will accelerate our efforts considerably.

More broadly, we’re continuing to grow our organization, while staying lean, focused, and highly adaptive through these critical stages of R&D. There are many programs in key stages of development, and we invite your readers to visit us at www.trillium.ag to learn more about our advances in crop protection.  

If you'd like to share your company's story and products/solutions. Please contact Grace Yuan via: grace@agropages.com

Join us to show your expertise in the coming issue!

Contact: joyce@agropages.com