30 January 2020

Deoptimize This

  • Adjuvant leads $22 million Series B financing for Codagenix
  • Proceeds will finance the development of Codagenix’s computational platform for synthetic codon deoptimization
  • Codagenix has multiple clinical stage candidates across infectious diseases, oncology, and animal health


The Science of the Synonymous

While there are 64 ways to arrange the four nucleotides adenine (A), thymine (T), guanine (G) and cytosine (C) into triplet codons, there are only 20 amino acids that codons can encode for. This means that certain amino acids can be encoded by several codons – as many as six. Codons that encode for the same amino acid are called synonymous codons.

Why are synonymous codons interesting? It turns out that certain codons – certain ways of arranging A, T, G, and C to create amino acids – are more efficient than others. These “better” codons thus show up in the wild in greater proportions than less efficient synonymous codons (there are varying theories as to why this is observed). For this reason, synthetic biology companies now offer tools to “optimize” sequences to increase yields of target gene products.

The ability to improve expression has the potential to make a meaningful difference in the manufacturing of biological products as well as for emerging strategies like DNA/RNA vaccines, which rely on host cells to generate antigens (the parts of a virus that interact with the body’s immune system) and other gene products to induce an immune response. Improving expression is a key technical hurdle for these kinds of vaccines. However, as is often the case in biology, things are more complicated than they seem. Emerging evidence suggests that codon optimization may reduce translational fidelity, increase unwanted immune reaction, and may have other unknown impacts on downstream protein structure and function[1]. These concerns have rightly cooled enthusiasm over codon optimization for human therapeutics.

[1]A critical analysis of codon optimization in human therapeutics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253638/




Slowing Down

If we can use optimal codons to increase the production of proteins we want, shouldn’t we also be able to use suboptimal codons to reduce the production of proteins and functions we don’t want?

The answer, it turns out, is yes.

We developed a unique appreciation for the prospective value of a “sub-optimal” approach (!?) during the diligence process for our most recent investment: a $10 million commitment to a $22 million Series B financing for Codagenix, a New York-based biotechnology company that has developed a novel codon deoptimization platform that enables the “rational” design of vaccines and oncolytic therapies. Codagenix’s vaccines are based on modified versions of wild-type viruses with hundreds of codons replaced with deoptimized, less efficient codons.




Re-Writing Vaccine Development

For decades, live attenuated viruses, that is, viruses that have been damaged or otherwise altered in order to cause an immune response but not disease) were behind many of the world’s most effective and important immunizations, including major public health victories such as the global control of horrible infectious diseases such as measles, yellow fever, and polio. Our bodies’ immune systems typically react best to vaccines that are most similar to the target pathogen; these weakened versions of the wild-type virus tend to induce the production of antibodies and other cellular defenses that are likely to protect us from the natural pathogen if we are unlucky enough to be exposed in day-to-day life.

Traditional live vaccines, however, have a number of imperfections, including that they can revert to virulence, that they necessitate challenging and antiquated manufacturing processes in many cases, and, most importantly, can require in the context of pandemic threats, long and expensive development timelines. Many live vaccines were developed as a result of “random point mutations to achieve attenuation. This means as few as five nucleotide changes can be achieved through unpredictable mutation-forcing techniques such as repeat passaging under sub-optimal conditions (e.g., under low temperatures or in an inefficient growth medium). While this approach worked well for some of the earliest commercial-scale vaccines, emerging supply and safety issues beg the question: can we make better vaccines?

Here’s where codon deoptimization can offer a vast improvement. Codagenix flips the live vaccine paradigm on its head, leveraging computational approaches and the rapidly falling cost of DNA synthesis to design live vaccines attenuated by increasing the number of less efficient codons. Because these vaccines are based on wild type genomes, they are easier to manufacture and more genetically stable than traditional live vaccines. Importantly, Codagenix’s approach allows it to develop entirely new vaccine candidates in a matter of months as opposed to years. Codagenix can order custom, deoptimized viral genomes and enter manufacturability and early animal testing in a number of weeks.

Tackling Disease X

As the world has globalized and barriers to trade and travel decreased, the chances of pandemic outbreaks have grown. This risk is playing out in real-time as we print this blog post, with 2019-nCoV exploding throughout mainland China despite historically unprecedented control efforts.

Add to this radically lowering costs and increasing simplicity of some of the most powerful biotechnologies ever developed – technologies which can allow rogue actors to create lethal new pathogens from scratch – and the potential for mass casualty pandemics has likely never been higher. Critically, we have no way of predicting which new pathogen will emerge naturally or be synthesized by our enemies, and therefore can’t stockpile the appropriate vaccines and medicines to fight them. Unknowable pathogens are often referred to as “Disease X”.

Governments around the world have made preparing for Disease X a top priority. Through government agencies like BARDA and multi-lateral consortiums like CEPI, there has never been more momentum and funding to support the technologies that would enable the rapid development of vaccines and treatments for emergent pathogens.

Codagenix’s technology could be a near-perfect ally in the fight to address the Disease X problem. After Disease X shows up, within weeks of its being sequenced and identified, Codagenix can evaluate multiple live deoptimized vaccine candidates. Like any other vaccine, these candidates would need to be tested for safety and efficacy, but the if the core technology paradigm for generating rationally-attenuated vaccine candidates can be proven to generate safe and stable viruses, the Codagenix platform could enable significantly faster development timelines compared to traditional approaches. Partnering with high-throughput innovative vaccine manufacturing companies could offer public health authorities the ability to rapidly develop new vaccines and manufacture large numbers of doses in relatively short order. Codagenix has already made significant early progress against these objectives and we look forward to helping further develop this vital public health capability.


What’s Next

We’re thrilled to partner with the Codagenix team to take their codon deoptimization technology deeper into the clinic and explore new indications in neglected infectious diseases and oncology. Our capital will be used to further ongoing human trials for the company’s influenza and RSV vaccines, as well as initiate the development of vaccines for two new neglected diseases. The Series B financing will also be used to enter the clinic with Codagenix’s oncolytic virus program, which uses the intra-tumoral injection of deoptimized viruses to stimulate the immune system to attack malignant cells. We couldn’t be happier to partner with the Codagenix team to advance the development of these important medicines and validate the company’s potentially game-changing codon deoptimization platform.