“The fact that proteins are not synthesized directly on genes demands the existence of an intermediate information carrier…which receives genetic information from the gene in the form of an unstable intermediate…a special type of RNA molecule, or ‘messenger RNA’.”
– Brenner, Jacobson, and Meselson et al, Nature, 1961
When the COVID pandemic hit, life-saving mRNA vaccines were suddenly thrust into the global spotlight. But the concept of using RNA–nature’s efficient, elegant biological “information carrier”–for patient benefit has both fascinated and humbled scientists for decades. In principle, RNA medicines could transform any cell in a patient’s body into a protein production factory of our choice. RNA could be used to train our immune system, replace missing proteins, reprogram cells, introduce genetic editors, and much more. RNA medicines could be programmable, personalizable, and yes–even “printed” at record speed.
In recent years, remarkable progress has been made in the RNA therapeutics field across many academic labs, biotech companies, and interdisciplinary teams. First-generation RNA medicines discharged a series of existential risks, including scaled RNA synthesis, delivery past the lipid bilayer, protection from RNA-degrading enzymes, and avoidance of immunogenicity. Over 12 billion doses of the COVID-19 mRNA vaccines have now been administered across 184 countries. Katalin Karikó and Drew Weissman (Orbital Therapeutics co-founder) were recognized with a 2021 Lasker Award for discovering mRNA modifications that avoid immune activation and improve protein production efficiency. The field of RNA medicines is now undergoing nothing short of a renaissance.
As often happens following fundamental technology breakthroughs in any field, we now see the pace of innovation in RNA medicines accelerating even further. (For other examples, think of the PC market after IBM; the biotech sector after Genentech pioneered the use of recombinant DNA; the field of AAV gene therapy following work done at CHOP/Spark towards a first approval; or most recently, the field of startups advancing generative AI applications after OpenAI’s launch of GPT-4.) Following early wins in the field, dozens of universities have created dedicated centers for RNA biology and therapeutics. Biopharma R&D investment in RNA-based modalities has continued to increase, and the pool of talented scientists with deep RNA expertise is quickly expanding. Regulatory familiarity with RNA medicines, too, is poised to catalyze further speed. These are all special tailwinds for startup founders–especially those who have been original innovators in the field.As often happens following fundamental technology breakthroughs in any field, we now see the pace of innovation in RNA medicines accelerating even further.
Enter Orbital Therapeutics, led by CEO Pino Ciaramella. Pino is an exceptional example of a founding CEO (a profile we love to back!) in biotech, whose own expertise allows the company to see around corners and build what Ben Horowitz calls a “knowledge pyramid” (see the linked blog post to drill into this). Prior to cofounding Orbital, Pino served as CSO at Beam Therapeutics (Orbital’s strategic partner and also a company with a deep bench of RNA capabilities–at Beam, base editors are introduced into cells as mRNA!). And prior to this, Pino was CSO of the infectious diseases division at Moderna, where he led the company’s initial mRNA vaccine pipeline and first IND submission. As we got to know Pino, we knew we had to back Orbital: he is science-first in his strategy, extremely product-focused, but also ambitious in his goals to build a first-in-kind RNA technology platform which leverages data science and automation at every step of the way. In our experience, this is a rare combination of traits.
Orbital is taking advantage of what is already known, but also innovating with urgency to make RNA-based therapeutics impactful and accessible for a much wider set of patients worldwide. In order to do this, the company has assembled a group of outstanding founders who bring core technologies that could solve some of the hardest outstanding challenges in the field, namely extending durability (needed to unlock new applications without frequent re-dosing), controlling immunogenicity, and achieving novel cell type access (especially extrahepatic tissue delivery).Orbital is taking advantage of what is already known, but also innovating with urgency to make RNA-based therapeutics impactful and accessible for a much wider set of patients worldwide.
We have known (and even previously backed!) several of the academic founders–in fact, we were also seed investors in CircBio, a technology company that Orbital has now acquired. We deeply respect the iterative engineering mindset that the team brings to key goals–the modular, high-throughput platform built to screen synthetic circular RNAs for extended durability in the Stanford lab of Orbital co-founder Howard Chang is a beautiful example, recognized recently on the cover of Nature Biotechnology (shown below!). Every single piece of an RNA medicine–from the RNA structure, to the regulatory sequences, to the delivery vehicles, to manufacturing–is amenable to screening, machine learning, and design optimization to tune in the exact therapeutic properties needed to unlock new clinical applications. These are an incredibly exciting set of engineering biology challenges to tackle.
It is a tremendous privilege to work with the Orbital founding team and investor syndicate, and to serve on the company’s board of directors. If the mission of building the future of RNA medicines excites you, consider joining our Orbit!