VDP-89 [Assessment]: ExcepGen Inc - RNA therapeutics for longevity

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VitaDAO Project Submission

Project Name: ExcepGen Inc

Project lead name: Thomas Folliard

Project lead email address: Thomas.folliard@excepgen.com

Lead organization website: Excepgen.com

Key personnel
Thomas Folliard (Chief Executive Officer)
Barbara Mertins (Chief Technology Officer)
Katherine Barcay (Chief Operating Officer)
Imre Mager (Head of R&D)
Jason Wojcechowskyj (Director of Vaccines)
Pragya Mukherjee (Scientist)

Describe what you’ll produce in 50 characters or less:
RNA therapeutics for longevity/age-related disease

Please provide a fuller description of what you are doing and how it will impact longevity/healthspan/lifespan

Next-generation vaccines with better efficacy and broader protection are critical for increasing longevity. Severe viral infections have been associated immune dysfunction and chronic inflammation that match signatures of premature aging, an effect that can persist even after the pathogen has been cleared. Moreover, seasonal infections are a common cause of life shortening, frequently even in otherwise healthy individuals. The NIH’s National Institute on Aging has categorized flu as a very serious and life-threatening disease for elderly adults. The respiratory illness caused by viral influenza infection caused more than 12,000 deaths in older Americans over age 65 in 2018. Now in the endemic phase of Covid-19, the risk that aging populations face from viral infections has never been greater.

ExcepGen is developing a new generation of vaccines and therapeutics with its RNAx platform. ExcepGen’s RNAx is delivered alongside primary RNA cargo. RNAx is translated by the cell to produce a regulator protein that modulates signals between the nucleus and the cytoplasm of cells in a tunable manner. By doing this, we keep cells in a low-stress state improving the effectiveness of the RNA cargo to produce significantly more protein leading to increased protection.

We are applying this technology to produce RNA vaccines for challenging antigens, such as universal flu antigens.

While industry-standard messenger (mRNA) was successful in producing a COVID-19 vaccine, this was partly possible because the Spike antigen is highly immunogenic. Other RNA vaccines that target more challenging viral antigens may require longer antigen expression and better immune engagement to be effective.

Self-amplifying RNA (saRNA) is a promising modality for eliciting broader immunogenicity and making better RNA-based vaccines, but it comes with a catch-22. On one hand: saRNA allows for greatly increased antigen expression, potentially requiring lower doses, increasing valences (number of encoded antigens), and providing better adaptive immune responses. On the other hand: its delivery and replication cause inflammatory intermediates and harmful innate signaling that counteract the potential benefits.

With ExcepGen technology, saRNA translation is protected from these cellular triggers. We have demonstrated that

I. saRNAx produces a 400% boost in cargo expression in vivo in mice compared to standard saRNA

II. saRNAx produces up to 2600% improvement in cargo expression in innate-immune-competent human BJ cells

III. saRNAx majorly reduces, and in some cases completely prevents, deleterious inflammatory cytokine release

Based on these exciting platform data, we are pursuing the holy grail of vaccines - a fully differentiated universal pan-flu vaccine that we believe can only be unlocked by saRNAx technology. This product is our primary focus for the vaccine space with additional pipeline products planned for vaccines, protein replacement, and gene-editing.

How far along are you? How close to having intellectual property are you? For projects that you don’t think require IP, please explain.

We expect that we have already generated significant IP and we expect that we have strong IP coverage. We have a portfolio of patent applications submitted by Cooley LLP to protect our core technology and its applications.

What are your competitive advantages over other research and people in your space?

Core technology mechanism: We identified a counterintuitive, holistic way to make RNA perform better. Because our mechanism is counterintuitive, others in the space have not already been exploiting it.

Synergistic technology: Our technology works across many RNA types so we can work with our own RNA modalities or those generated by Pharma partners (including linear and self-amplifying, modified and unmodified, etc.)

IP Strategy: We have applied our technology broadly across RNA types and other nucleic acids to demonstrate our key benefits. We kept the company in stealth mode while developing our strong IP portfolio, which now gives us a strong foundation for technology partnerships in the RNA space.

Nimbleness: We are a small team and we can iterate quickly. Our research process enables rapid in vitro and in vivo testing and refinement.

Why did you pick this area to work on? Briefly discuss your domain expertise. How do you know people need specifically what you’re making?

Severe viral infections have been associated immune dysfunction and chronic inflammation that match signatures of premature aging, an effect that can persist even after the pathogen has been cleared.

The company founding team has deep technical expertise engineering reliability into biology for use in unreliable environments such as in microgravity and the rhizosphere. Educated at top universities, the co-founding team met at Oxford university and founded ExcepGen to engineer reliability into genetic medicines.

We know people need specifically what we are making because of the number of major mRNA companies looking to evaluate our technology for licensing.

What is it about your approach or your findings that you think others don’t understand? What’s new about it and/or surprises people the most when they hear about it?

We encode RNA to produce a regulator protein that makes cells amenable to RNA instructions, resulting in majorly increased cargo expression and prevention of unwanted innate signaling and inflammatory responses. The regulator works by dampening transport of signals between the nucleus and the cytoplasm. Others think this sounds like it would be detrimental to RNA translation and cell function. Counterintuitively, by dampening that “information highway” for the cell, we actually prevent stress signaling and innate immune signaling. The expected MOA is that stress signals are activated when certain cell signaling pathways rise above “normal” signal thresholds. By slowing down the flow of information, ExcepGen technology makes cells amenable to executing the instructions they have been given. We believe that this technology will open up a whole new world of RNA drugs across vaccines and oncology.

Briefly explain how you will spend the money we would give you. This can be as simple as an itemized list of your costs.

ExcepGen is currently applying its technology to vaccines. An assessment from VitaDAO would fund in vitro research, scientific operations, and an in vivo immunogenicity study.

Any other project ideas or IP you’d like us to consider?
No

How did you hear about VitaDAO?
Pfizer - Mike Baran

  • Agree
  • Needs Revision
  • Disagree

0 voters

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Some additional context: at Pfizer we have been talking with Tom and the ExcepGen team for 6 months+ and are intrigued by the technology. As most are all likely aware RNA therapeutics is one of the most promising modalities in therapeutic development. One of the engineering challenges to delivering RNA is maximizing its durability against the innate immune response which is actively trying to clear the foreign nucleic acid.

The ExcepGen technology potentially stabilizes LNP delivered RNA, leading to longer half-life and longer expression of payload. While the pilot project proposed for VitaDAO would be to explore in the context of a Universal Influenza Vaccine, the technology would be applicable beyond vaccines and of potential benefit to future drug discovery programs.

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Any more info to share on the specific ask?

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There’s not a lot of data presented here to assess (or budget… is this a $100k ask, $250k ask, more?). Is the WG’s assessment forthcoming on this proposal? And are we voting on the proposal itself, or the WG’s assessment of it?

It sounds like the company is expressing either an NF-KB/IRF inhibitor or some kind of Ran GAP along with the saRNA. Once the patent filing becomes public, it would be help the assessment to have at least a ballpark idea of which pathways are being targeted. Are there any papers published showing this blockade does not lead to cell toxicity?

I can see how increasing mRNA survival/half-life will increase expression. Better expression means lower doses, means lower off-target effects, which is all good. But I thought the limiting factor is on-target effects-- engaging innate sensors like TLR7, NLRP3, RIG-I, MAVS, etc. Nor am I convinced that extending expression time would enhance vaccine outcomes.

My understanding is that the limiting inflammation for LNP delivered RNA is caused by activation of cytosolic innate sensors, and the LNP composition was as much a part of it as the RNA. Or did I read too much into Ira Mellman’s Nature Immunology paper from last year (PMID: 35332327)?

I also thought the limiting issue for flu vaccine efficacy in the elderly is the lack of an immune response. I am not convinced higher dosing is the long-term fix-- part of the immune system is broken in old people, and that’s where the longevity problem is.

It’s also not clear to me how this approach will generate a universal flu vaccine. Longer-lasting RNA doesn’t fix antigenic drift.

Also some concerns about model systems. If they’re going for a flu vaccine, mice are not a good model system. Fibroblasts like BJ cells might be a starting point, but I thought the main in vivo targets for an intra-muscular vaccine are muscle cells and any macrophages/DCs nearby. Macs and DCs have way more antiviral sensors than a fibroblast.

Why was “universal flu vaccine” considered the best target to pursue, even in the vaccine space? Seems like encoding an anti-HIV ribozyme, going after some other latent virus, or extending expression of a therapeutic you want expressed for a medium-ish time period (what is the t1/2 for expression vs AAV, regular RNA-LNP, or other delivery methods?) would be better choices.

Or in the longevity space, what about reprogramming sensencent cells?

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Thanks Michael - I have asked Tom to supply their Non-conf presentation as well as a project plan with milestones/budget

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Great feedback Shrike - and agree there is no data shared to assess. Will add in a non-conf to give a better sense what they are doing + detailed project plan and budget.

High level the budget will be to support further in-vivo PoC for universal influence Vx + self amplifying RNA (saRNA) in an animal model. Success defined as showing prolonged expression and titer.

Will get Excepgen to answer your questions - but first pass from me below:

There’s not a lot of data presented here to assess (or budget… is this a $100k ask, $250k ask, more?). Is the WG’s assessment forthcoming on this proposal? And are we voting on the proposal itself, or the WG’s assessment of it?

Will post a non-conf deck with data. We are in process of pulling together a senior reviewer team. Internally at Pfizer this one has passed diligence review and we are looking to move forward with our own project. A few others pharma may be moving to MTA as well.

It sounds like the company is expressing either an NF-KB/IRF inhibitor or some kind of Ran GAP along with the saRNA. Once the patent filing becomes public, it would be help the assessment to have at least a ballpark idea of which pathways are being targeted. Are there any papers published showing this blockade does not lead to cell toxicity?

Target has not been made public. The ompany can provide more detail on MOA.

I can see how increasing mRNA survival/half-life will increase expression. Better expression means lower doses, means lower off-target effects, which is all good. But I thought the limiting factor is on-target effects-- engaging innate sensors like TLR7, NLRP3, RIG-I, MAVS, etc. Nor am I convinced that extending expression time would enhance vaccine outcomes.

You describe the approach well. This approach essentially blocks nuclear transport. So the innate sensors you describe would initiate transcription of the immune cascade in the nucleus to a lower extent & their transcripts would be trapped/or export minimized therefore lowering translation of immune machinery in the cytoplasm, which would then lead to longer RNA half life.

Our thinking at Pfizer is that this is potentially a way to overcome the challenges to date with self amplifying RNA. saRNA is believed to be one of the approaches to tackle the problem of RNA stability. (Others are excited by circular RNA). It is believed overcoming immunogenicity is one of the limiting factors to success with saRNA & this technology has potential to overcome that challenge.

My understanding is that the limiting inflammation for LNP delivered RNA is caused by activation of cytosolic innate sensors, and the LNP composition was as much a part of it as the RNA. Or did I read too much into Ira Mellman’s Nature Immunology paper from last year (PMID: 35332327)?

You are correct - the contribution of inflammation comes from both LNP & nucleic acid. Although nexgen lipid formulations are designed to minimize.

I also thought the limiting issue for flu vaccine efficacy in the elderly is the lack of an immune response. I am not convinced higher dosing is the long-term fix-- part of the immune system is broken in old people, and that’s where the longevity problem is.

This may be true. But also achieving high titer against a cocktail or potentially inclusive antigen should also have efficacy.

It’s also not clear to me how this approach will generate a universal flu vaccine. Longer-lasting RNA doesn’t fix antigenic drift.

Will get you the detail on this. The POC experiment will include a well published construct.

Also some concerns about model systems. If they’re going for a flu vaccine, mice are not a good model system. Fibroblasts like BJ cells might be a starting point, but I thought the main in vivo targets for an intra-muscular vaccine are muscle cells and any macrophages/DCs nearby. Macs and DCs have way more antiviral sensors than a fibroblast.

Will get you detail on this from the company.

Why was “universal flu vaccine” considered the best target to pursue, even in the vaccine space? Seems like encoding an anti-HIV ribozyme, going after some other latent virus, or extending expression of a therapeutic you want expressed for a medium-ish time period (what is the t1/2 for expression vs AAV, regular RNA-LNP, or other delivery methods?) would be better choices.

Will get an answer from company on this.

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I look forward to the company’s answers.

Improving RNA stability is a no-brainer for Pfizer and competitors if it looks like it might work. Lot of applications, which is why the current choice of target is somewhat mystifying.

In the meantime, two more concerns. The highest level view is that Excepgen is trying to reinvent RNA viruses. Since RNA viruses already exist, is Excepgen’s pathway already targeted by RNA viruses? If not, a big question would be why not? Do the viruses target a related part of the pathway, or did they give up on this mode of control?

Related to that, inflammasome activation doesn’t require nuclear access to destroy a cell, and necroptosis is the back-up cytoplasmic death mechanism characterized both for Casp8 failure, but also during flu infection. The cell studies need to be able to test if necroptosis, pyroptosis (and PANoptosis if we’re keeping with current fads), ferroptosis, or autophagy will be activated. Fibroblasts are inadequate to test most of those hypotheses.

Or will they need to encode Gasdermin and RIP kinase/mlkl inhibitors in as well? …and/or encapsulate something like MCC950?

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