# HSCI-supported research leads to new class of therapeutics

December 13, 2018

## Summary

• Derrick Rossi’s research into using mRNA as a new kind of therapeutic was initially supported by HSCI seed funding, and gave rise to biotech company Moderna Therapeutics.
• Moderna’s public offering of $600 million is the largest ever of a venture-capital-backed biotechnology company, reflecting the potential of its new technology: mRNA therapeutics • Moderna’s success in creating therapies that will benefit patients reflects the crucial role of HSCI in enabling early-stage, high-risk research. Derrick Rossi’s exploratory research into using messenger RNA as a new kind of therapeutic was made possible by seed funding from Harvard Stem Cell Institute (HSCI). Now Moderna, the company he co-founded, has 10 of its programs and 20 products in clinical trials. On 7 December 2018, they launched the largest-ever initial public offering (IPO) of a venture-backed biotech company. The success of Moderna reflects the long-term value of backing early-stage, high-risk research. Without HSCI’s support, the mRNA technology that Rossi invented might have floundered. Instead, Rossi was able to develop his ideas into a practical solution that gained the attention of investors. That enabled him to start a company that is on its way to bringing a new class of treatments to patients. ## Bypassing DNA Messenger RNA (mRNA) is an intermediary. It converts the instructions in DNA into proteins: everything from insulin that helps convert food into energy, to antibodies that fight infection. In order to function properly, a protein needs to have the right sequence and shape. But if a gene is damaged, the mRNA might not be able to carry out the correct instructions for making a protein properly. Rather than inserting genes into target cells to fix a patient’s DNA, Rossi’s goal was to insert mRNA with the right instructions for creating healthy proteins. The challenge was to introduce those instructions into the cell without setting off alarms. “When you introduce RNA into a cell, the cell responds as it is being infected by an RNA virus. The cell goes into defense-mode shutting down cellular functions through a massive “anti-viral” response. It will even self-destruct to prevent the ‘virus’ from replicating – and that is the last thing you want if the goal is to have the introduced mRNA encode therapeutic proteins,” said Rossi. Rossi’s approach gets around this antiviral response by modifying the mRNA to appear like the patient’s own. Once the target protein is identified, researchers can reverse-engineer the corresponding modified-mRNA that can be introduced into cells without eliciting the antiviral response. According to Rossi, the new, improved mRNA can be ‘read’ by a patient’s own ribosomes – cellular machines that manufacture proteins – and turned into healthy proteins efficiently, without causing any adverse reactions in the cells. ## More than meets the eye “When I first presented the project to HSCI, we wanted to make a better tool for stem cell research. The idea was to find a new methodology for making induced pluripotent stem cells (iPS cells), using mRNA. The technology we developed ended up being so much more than that.” Rossi’s original concept was to make iPS cells without interfering with the genome, by using mRNA that the cell would recognize as its own. “We found a way to render mRNA invisible to the immune alarm systems of the cell, and that was the key to turning mature cells into iPS cells efficiently.” For Rossi and his colleagues, moving around a cell’s fate with their new technology may have got a lot of attention, but wasn’t the most interesting part of their findings. “What was really exciting was seeing how we could make any protein with this technology – because if that was possible, we would have a whole new therapeutic paradigm. Defective proteins underlie much of human disease, and here we had a technology that would allow us to fix those proteins,” he said. Since its inception, Moderna has focused on using their ‘modified RNA’ platform as a treatment paradigm for patients. By introducing mRNA that will make the right protein to address different diseases, they hope to achieve a whole new approach to therapeutics. ## Target practice Almost all diseases with a genetic basis have a corresponding protein deficiency. But so many different proteins are potential targets that a broad array of mRNA therapies would be needed – each of which would address a specific cell type. The two main challenges to overcome involve delivery: getting these large molecules into a cell efficiently, and figuring out the right dose. Moderna is addressing this by developing several different delivery methods. Their goal is to determine the precise dose needed to get high levels of proteins (but not too high) made on a regular basis. So far, the results of their research are quite promising. ### Moderna at a glance • Co-founded by Derrick Rossi, Kenneth R. Chien, and Robert Langer. • Based on initial research supported by HSCI. • 10 research programs have entered clinical studies. •$1.6 billion in venture funding received before IPO.

• Major stakeholders: AstraZeneca, Flagship Pioneering, Merck, Vertex Pharmaceuticals.

## Keeping the discovery pipeline open

“When I met with Doug Melton about our project, he saw right away that it was going to be potentially transformative,” recalled Rossi. “He also realized it was so exploratory that we wouldn’t be able to get it funded through the regular channels. He suggested I apply to HSCI, which I did, and we got seed funding.”

“Our real breakthrough touched on a huge unmet clinical need; a lot of patients are in desperate need of specific types of proteins to treat their illness. But remember – that wasn’t what we set out to do. This is often how science works: you think you’re working on one thing, and it turns out you’re working on something else,” said Rossi.

Following the landmark publication, Flagship Ventures (now Flagship Pioneering) provided venture capital. Rossi joined forces with Kenneth R. Chien of Harvard and Robert Langer of MIT to found Moderna, so they could further develop their mRNA technology. Tim Springer of Harvard, himself a successful entrepreneur, was the first investor that Rossi secured for Moderna Therapeutics.

Investors have been confident in the potential of Moderna’s technology for creating transformative treatments: the company has raised more private funding than any other biotech to date. Moderna’s valuation at its IPO of over \$10 bn further underscores the transformative nature of the science on which it is based.

HSCI executive director Brock Reeve said, “A key tenet of HSCI is to fund early-stage research that has high risk but great potential for reward. When HSCI gives outstanding, innovative, and imaginative scientists like Derrick Rossi seed grant support, it can change a field quickly and dramatically. Rossi's initial exploratory idea has transformed into so much more: a technology that could make a real difference to patients and their families.”