“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. Click To Tweet
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. Click To Tweet
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!
The views expressed here are those of the individual AH Capital Management, L.L.C. (“a16z”) personnel quoted and are not the views of a16z or its affiliates. Certain information contained in here has been obtained from third-party sources, including from portfolio companies of funds managed by a16z. While taken from sources believed to be reliable, a16z has not independently verified such information and makes no representations about the enduring accuracy of the information or its appropriateness for a given situation. In addition, this content may include third-party advertisements; a16z has not reviewed such advertisements and does not endorse any advertising content contained therein.
This content is provided for informational purposes only, and should not be relied upon as legal, business, investment, or tax advice. You should consult your own advisers as to those matters. References to any securities or digital assets are for illustrative purposes only, and do not constitute an investment recommendation or offer to provide investment advisory services. Furthermore, this content is not directed at nor intended for use by any investors or prospective investors, and may not under any circumstances be relied upon when making a decision to invest in any fund managed by a16z. (An offering to invest in an a16z fund will be made only by the private placement memorandum, subscription agreement, and other relevant documentation of any such fund and should be read in their entirety.) Any investments or portfolio companies mentioned, referred to, or described are not representative of all investments in vehicles managed by a16z, and there can be no assurance that the investments will be profitable or that other investments made in the future will have similar characteristics or results. A list of investments made by funds managed by Andreessen Horowitz (excluding investments for which the issuer has not provided permission for a16z to disclose publicly as well as unannounced investments in publicly traded digital assets) is available at https://a16z.com/investments/.
Charts and graphs provided within are for informational purposes solely and should not be relied upon when making any investment decision. Past performance is not indicative of future results. The content speaks only as of the date indicated. Any projections, estimates, forecasts, targets, prospects, and/or opinions expressed in these materials are subject to change without notice and may differ or be contrary to opinions expressed by others. Please see https://a16z.com/disclosures for additional important information.