Design and testing of broad-spectrum antivirals

EDIT: The R&D expenses for this project have now been fully funded for $150,000 by another funder. Given that the project is projected to cost $300,000 total including salary/benefits/consulting costs, the project is still open to receiving further funding to cover these personnel costs.

Project summary

Panoplia Laboratories is a new nonprofit organization based in Cambridge, Massachusetts performing research into broad-spectrum medicines to counter pandemics. We aim to develop medicines that offer long-lasting prophylactic protection, similar to vaccines, but in a pathogen-agnostic manner. Such medicines could be produced and stockpiled in advance of the next pandemic, ready to be deployed at the start of an outbreak regardless of the identity of the pathogen. Our approach is fundamentally proactive with a broad reach rather than reactive and specific to only certain pathogens.

The first drug candidates we will investigate are based on antivirals known as DRACOs, which were previously shown to exhibit broad activity against viruses across 10/10 families tested in cells and 3/3 families tested in mice (only ~25 viral families are known to infect humans). DRACOs work by initiating programmed cell death in infected cells, containing the spread of infection. Their broad mechanism of action suggests they could be effective against nearly all viruses.

While early research on DRACOs was promising, they were never advanced as drugs, since they would be difficult to deliver into cells and would be rapidly cleared from the body. We aim to improve upon the initial DRACO research by encoding DRACO-like molecules in DNA, which will enable us to employ new strategies for drug delivery and allow for longer-lasting activity. If successful, our project could launch the development of a drug that could prevent nearly all respiratory infections for months with a single dose.

What are this project's goals and how will you achieve them?

The goal of this project is to conduct scientific research demonstrating safety and efficacy of DNA-encoded DRACO-like molecules delivered to the lung. We are aiming for these antivirals to provide months-long prophylactic protection against a broad set of respiratory viruses.

We expect our initial research project to be split into two phases, each around 3 months in length. Phase 1 will consist of drug design, manufacturing, testing in cell culture, and preliminary drug delivery experiments in model systems. A successful outcome of Phase 1 would be to have:

Designed and manufactured at least 20 antiviral candidates
Tested all candidates in cell culture models for safety and efficacy, producing at least one lead candidate to take forward into Phase 2 experiments
Tested at least 3 formulations with a lung-compatible route of administration device in lung tissue, producing at least one formulation with high prospects for efficient in vivo lung delivery

Phase 2 will consist of more extensive animal study work including challenge experiments in which we will assess our drug’s ability to protect small rodents from virus infection. A successful outcome of Phase 2 would be:

To have shown a significant reduction in clinical signs (e.g., weight loss) in response to a virus infection
To have demonstrated protection from infection when the drug has been administered at least one month prior to the virus challenge

How will this funding be used?

We are asking for $150,000 to cover research & development and operating expenses, including salaries for 3 scientists. We would use this funding to cover either of two 3 month-long research phases, depending on the success of other funding applications we are making.

Phase 1 cost estimates:

Funding goal: $150,000
-$65K for salary/benefits/taxes for 3 scientists for 3 months
-$2K for consulting experts for feedback on research plan
-$18K for three months of laboratory rent
-$15K for DNA production and testing in cell culture
-$30K for formulation procurement and screening
-$20K for drug persistence evaluation

Phase 2 cost estimates:

Who is on your team and what's your track record on similar projects?

Our team consists of myself and three scientists.

I (Brian Wang) previously managed this same team for 1 year as the Head of R&D at Alvea, where together we designed, produced, and tested in animals several RNA vaccine candidates against COVID-19 and influenza. In addition, I designed a DNA vaccine candidate at Alvea that entered Phase 1 clinical trials within 6 months—likely the fastest time from company formation to clinical trial initiation in history. Prior to Alvea, I completed a postdoc with Kevin Esvelt at the MIT Media Lab, where I helped develop a directed evolution platform, design and test a COVID-19 drug candidate, and validate a DNA synthesis screening procedure for biosecurity.

Our lead scientist, Joe Torres, has a PhD in Molecular and Cell Biology with >10 years of lab experience in immunology and virology. Our other two scientists, Alex Kleinman and Alex Norman, made key contributions to vaccine development projects at Alvea.

What are the most likely causes and outcomes if this project fails? (premortem)

While we have de-risked our plans by talking to expert consultants and conducting literature analysis, there still remains significant technical risk around the safety, efficacy, and persistence of the drug candidates we wish to test, which can only be reduced further through experimentation. We are uncertain whether:

Our drug candidates would be sufficiently nontoxic in vivo when persistently expressed
We could efficiently deliver enough drug to the respiratory tract to be maximally effective
Our drug candidates would be persistently expressed at a high enough level to deliver months-long protection

If this particular project fails, we would likely attempt to troubleshoot and examine the causes of failure. If we determined that further iterations on our candidates would have a significantly higher chance of success, we would try those.

What other funding are you or your project getting?

We have acquired some seed funding to sustain our initial activities; we could use these funds for this project, but at a significant cost to our runway. We have applied to the Survival and Flourishing Fund and the Long-Term Future Fund for similar projects (although different in scope), and are currently considering several other opportunities for funding. Please contact brian.wang@panoplialabs.org for more information.