VDP-18: Jonathan An- Towards reversing periodontal disease using Geroscience

Proposals Passed Proposals
1

Longevity Working Group short report

Longevity Dealflow team

Scientific evaluation : Jason Colasanti, Ariella Coler-Reilly, Tyler Golato and 2 anonymous reviewers (professor)
Business evaluation : Tim Peterson, Sara Ramos Colmenarejo
Shepherd : Estéfano Pinilla

Project PI : Dr Jonathan An

Simple Summary

Periodontal disease (periodontitis) is a chronic oral disease impacting over 70% of older adults, where inflammation of the tissues supporting the teeth results in loss of connective tissue attachment, bone, and ultimately the tooth. The greatest underlying risk factor for periodontitis is age, and its association with other age-related diseases, such as heart disease, diabetes, and Alzheimer disease, highlights the importance of incorporating this oral disease in geroscience studies. Jonathan An’s lab proposes to test a series of compounds targeting inflammation in a mouse model of age-related periodontitis, with the goal of finding a geroscience-based treatment for this neglected disease that has a severe impact on human healthspan.

Problem

Efforts to slow the progression of periodontitis in older adults have been attempted through various therapies, including scaling and root planing (“deep cleanings”) or antibacterial adjuncts to reduce pathogens in the pocket, but these treatment modalities are invasive, need to be repeated often, and rely on access to such modalities, which may be limited for many older adults. Furthermore, current therapies are limited to treating the symptoms and fail to address the underlying cellular and molecular causes of periodontal disease, which we hypothesize are a direct consequence of biological aging.

Opportunity

A component in most age-related disease and decline is a low-grade, chronic inflammation without overt infection known as “inflammaging”. Among the various organ systems that undergo inflammaging, periodontal disease involves most, if not all, sources and outcomes of inflammaging. Thus, evaluating pathways that target “inflammaging” may provide a unique, Geroscience-based treatment modality to reverse periodontal disease. This novel approach to treat periodontal disease is expected to establish the first medical, non-surgical treatment for an age-related oral disease. Moreover, this approach to treat periodontal loss is expected to have a positive impact on age-related cognitive decline.

Jonathan An’s Lab proposes to use small molecule inhibitors of the PI3K/NFkB/mTOR pathway to treat periodontal disease, and will test 5 candidates administered orally in the chow in an 8-week study, using rapamycin as a positive control. The drugs have well established pharmacokinetics and pharmacology since they have been investigated for other indications.

If this first study demonstrates that any of the small molecules is effective in reversing periodontal disease when administered systemically, a second sub-study will be carried out to test the effectiveness of their local delivery by brushing the interventions across the gum line, comparing them with locally delivered rapamycin.

The proposal is mainly based on a recent eLife paper (Rapamycin rejuvenates oral health in aging mice | eLife) by the research group, where they find positive effects of 8-week treatment with oral rapamycin in age-related periodontal bone loss in mice. The proposed interventions have never been before tested in the context of aging and periodontal disease. Johnathan An’s Lab envision improvement of the periodontal disease phenotype after 8-week treatment with the candidate compounds maybe a result of (1) an improvement of systemic “inflammaging” to impact periodontal disease that will be tested with the first study, or (2) a direct improvement of periodontal disease, which will be tested with the second study. Either result could be the base for novel IP regarding formulation and/or delivery methods to improve aging, inflammation, and periodontal disease. Jonathan An’s collaborators also have preliminary data showing that a few of the tested interventions have beneficial effects on neurodegeneration and cognitive decline. Therefore, besides periodontal bone loss, the study will address effects on cognitive function and lifespan.

Results from the proposed study will provide critical pre-clinical IP data to support a future company targeting periodontal disease through geroscience, which the investigator(s) intend to spin out with support from VitaDAO.

IP Roadmap

If any of the locally administered treatments reverses periodontal disease, Jonathan An’s team envision the following path towards IP:

  • Localized Delivery of Compound X to Oral Cavity
    • To treat (indications):
      • Age-related periodontal disease in older adults
      • Peri-implantitis (periodontal disease of implants) in older adults
    • Method 1: Compound X Toothpaste
      • Prescription (from the dental office or medical office)
      • Over the counter (in low doses)
    • Method 2: Direct Delivery of Compound X to periodontal pockets with periodontal disease
      • IP surrounding both formulation and delivery mode
      • Completed in dental offices (medical offices)
      • Example : Local delivery of antimicrobial compounds, Arestin Ò
    • Method 3: Compund X trays
      • Example: Whitening trays

If Jonathan An’s Lab observes an effect in lifespan and healthspan, additional test of feasibility and safety in other mammalian models (i.e., non-human primates) will begin for application in clinic to target aging.

Team

Jonathan An: Project Lead, Assistant Professor at University of Washington. (Jonathan An - Healthy Aging and Longevity Research Institute)

Matt Kaeberlein: Professor at University of Washington. He will assess the long term healthspan and lifespan of mice after drug interventions. (Matt Kaeberlein, PhD | Faculty | Dept. of Laboratory Medicine & Pathology | UW Medicine)

Simon Johnson: Collaborator to evaluate the brain aging biology in the same animals with periodontal disease, Assistant Professor at University of Washington. Experienced researcher in the field of Neurology. (Simon C. Johnson, PhD) He will assess improvements in neurodegeneration and cognition due to treated periodontal disease.

Budget

  • Animal Ordering and Facility Cost: $120,443.80
  • Research Staff: $68,230.00
  • Inflammatory Panels and Antibodies: $25,392.0
  • General Laboratory Consumables and Drug Costs: $15,000.00
  • microCT usage: $10,150.00
  • FTE for all personnel combined: $10,784.20

TOTAL: $250,000.00 - $300,000.00 (including TTO overhead)

Highlights

  • Periodontitis is an unmet need with great impact on healthspan.
  • Geroscience approach focused on inflammaging might have an impact in other age-related diseases as well as in cognitive decline.
  • Potential discovery of other targets in the PI3K/NFkB/mTOR pathway besides mTOR to increase lifespan.
  • High feasibility: Good experimental model established within laboratory and straight-forward research plan.
  • Repurposing study: Easier transition to clinical trials.
  • The project lead has access to a dental clinic that would accelerate setting up human studies in the future
  • Young investigator with interest to spin-out in collaboration with VitaDAO and backed by strong team.

Risks

  • Team lead lacks previous entrepreneurial experience.
  • The patents generated by this proposal would not be novel composition of matter, which is the strongest type of IP.
  • Product development pathway requires partnerships
  • Periodontal outcomes may not be broadly extrapolate to ageing in general

Outcome of the evaluation and recommendation

Of all the evaluators, 4 independently scored the project proposal on different categories as either: (1) Oustanding, (2) Strong, (3) Satisfactory, (4) Weak, (5) Unacceptable, (N/A) Not enough information provided, or (N/A) Not my area of expertise. This is a summary of the results:

  • Novelty and Impact: (2) Strong (4/4 evaluators)
  • Feasibility and Data: (2) Strong (3/4 evaluators); (3) Satisfactory (1/3 evaluators)
  • Relevance to longevity: (1) Outstanding (1/4 evaluators); (2) Strong (3/4 evaluators)
  • Science Team: (1) Outstanding (1/4 evaluators), (2) Strong (3/4 evaluators)
  • Market Advantage: (2) Strong (2/4 evaluators); (3) Satisfactory (2/4 evaluators)
  • IP-NFT Potential: (1) Outstanding (2/4 evaluators); (2) Strong (2/4 evaluators)

All the evaluators consider the project worth funding by the VitaDAO community

Mechanism of funding

This proposal recommends VitaDAO commits funding via an IP-NFT.

  • Agree
  • Agree with revisions (please comment)
  • Disagree

0 voters

9 Likes
2

Excellent write-up on a promising project!

Critical to me voting “yes” will be what the IP strategy looks like. Having 5 candidates is not sufficient as a strategy. There needs to be methods of use, formulations, and/or novel compositions of matter clearly defined ahead of us funding this project.

Regarding methods of use, is periodontitis treated with any drugs? What’s best in class currently? Because it’s not an acutely fatal condition and the drug would need to be taken chronically I would imagine the safety bar would be extremely high for any drug getting approved in this space.

Regarding formulations, one could imagine putting one of their compounds in toothpaste. That seems like the lowest hanging fruit idea to me.

Regarding the science, two minor issues: periodontitis I wouldn’t say is yet a bona fide cause of Neurodegeneration or other non-oral aging-related disease. There’s no connection between taking a drug systemically and fixing periodontitis and fixing any other disease. Those two outcomes aren’t necessarily related.

4 Likes
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Second this, the proposal mentions:

We are currently in conversations with the project lead and a more detailed IP strategy will be presented before the application becomes open for Phase 2 voting.

Could this be made available?

Regarding methods of use, is periodontitis treated with any drugs?

My understanding is mostly topical (gels or rinses) or oral forms of antibiotics, and topical forms of steroids

Some random data from NHS Dental prescriptions '17-'20

image
image2246×1312 474 KB

62% of all NHS dental prescriptions are for antibiotics, unfortunately this dataset doesn’t have the break down of if this was for gingivitis, periodontitis or some other procedure such as a post-op care.

Publications from the PI:

Rapamycin rejuvenates oral health in aging mice

JY An, KA Kerns, A Ouellette, L Robinson, HD Morris… - Elife, 2020 - elifesciences.org

Periodontal disease is an age-associated disorder clinically defined by periodontal bone
loss, inflammation of the specialized tissues that surround and support the tooth, and
microbiome dysbiosis. Currently, there is no therapy for reversing periodontal disease, and …

Cited by 24 Related articles All 11 versions

[HTML] nih.gov

Rapamycin treatment attenuates age-associated periodontitis in mice

JY An, EK Quarles, S Mekvanich, A Kang, A Liu… - Geroscience, 2017 - Springer

Interventions that target biological mechanisms of aging have great potential to enhance
quality of life by delaying morbidity and mortality. The FDA-approved drug rapamycin is a
compelling candidate for such an intervention. In a previous study, it was reported that 3 …

Cited by 49 Related articles All 8 versions

[HTML] nih.gov

Oral health in geroscience: animal models and the aging oral cavity

JY An, R Darveau, M Kaeberlein - Geroscience, 2018 - Springer

Age is the single greatest risk factor for many diseases, including oral diseases. Despite this,
a majority of preclinical oral health research has not adequately considered the importance
of aging in research aimed at the mechanistic understanding of oral disease. Here, we have …

Cited by 29 Related articles All 8 versions

6 Likes
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From Longevity-WG this meeting will be on 2021-12-20T05:00:00Z

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Thanks for updating with the date of the meeting, Ben. I’ve edited the proposal to include it. And just to clarify, the plans discussed during the meeting will be included in the proposal before the poll opens.

4 Likes
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I have edited the proposal to include the feedback from the comments above as well as the IP Roadmap provided by the project lead as a result of the meeting on 2021-12-19T23:00:00Z. I have also included a price range in the budget to give some room for negotiation with the TTO as @tylergolato has proposed in other posts (see: VDP-16: Korolchuk Lab- Autophagy Activators Funding Proposal - #8 by tylergolato).

With this changes, the proposal is open for community vote.

1 Like
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From the proposal it’s not clear if treatment will be topical or not. Looking at the IP strategy it seems to be localized delivery. Why is the team not exploring Pexidartinib systematically vs oral application?

In the eLife paper that describes positive effects on age-related periodontal bone loss in mice, rapamycin is administered in the feed (systematically). So improvements in age-related periodontal bone is possibly through an improvement of systemic “inflammaging”.

Oral approach limits exposure to drug but may not affect systemic inflammaging. Hence treating periodontis locally may solve that specific condition but not address the underlying low grade inflammation, that is a risk factor for many other chronic conditions including diabetes, cardiovascular, etc. including periodontis. Chicken or the egg?

3 Likes
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Welcome to Discourse Koen! Thanks for the great input. The administration route of the compound in the proposed study will be systemic in the chow, as in the eLife study with Rapamycin.

You are right to point out that local administration in the oral cavity will limit systemic exposure to the drug and most likely reduce the potential systemic anti-inflammatory effects. However, it’s important to consider two points:

  1. The effect of either the compound or the other 4 inhibitors of the PI3K/NFkB/mTOR pathway in inflammaging and lifespan (nor periodontal disease for that matter) hasn’t been investigated until now. This is why in addition to periodontal bone loss, Jonathan An’s lab plans to address the effects on cognitive function and lifespan.

  2. The regulatory pathway for locally acting formulations is easier, despite being less interesting for potential effects in lifespan. As I understand from the meetings with the lead investigator, if the treatment is successful for periodontal disease and they observe an increase in lifespan, both IP for local delivery and further feasibility/safety tests in other mammalian models to treat aging-related diseases will be explored in parallel.

I will try to re-write the proposal to clarify the points you have raised.

1 Like
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Great points @kdl. More studies to show any of the 5 compounds delivered systemically is probably not worth funding as there is no IP for that at the moment.

Also, these pathways are cancer pathways. One would expect major toxicity if given systemically. If given locally in the oral cavity, one would worry about their immune suppressive potential. This would compromise the mouth’s ability to fight off the infections that are the source of the problem.

It doesn’t make sense to fund V2 of the eLife paper. The experiments have to be directed on a commercializable path.

1 Like
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To answer to @kdl and @timrpeterson above, I worked with the project lead to include a local delivery treatment group in the experimental plan so the experiments are directed towards the commercializable path outlined in the IP roadmap.

I have modified the proposal to incluse these changes.

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By naming the compound and target pathway the IP has been made vulnerable. I propose there should be another screening process and an undisclosed short list of candidates decided upon that will be tested in formulations before deciding on a lead compound for the most in depth analyses.

There’s no reason a wide range of other compounds couldn’t be considered. In fact using PI3K inhibitors won’t be seen as desirable by pharma as there is a long history of failure with drugs targeting that pathway.

1 Like
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I’ve talked with the lead investigator and the compound that has been specifically mentioned can be substituted for others, the rest of compounds (not all targeted against PI3K) haven’t been publically disclosed and Jonathan An’s lab has promising preliminary data that supports their inclusion.

I’ve modified the proposal so no specific intervention is mentioned.

2 Likes
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Thanks! I now feel comfortable to upvote this project.

2 Likes
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This proposal is now live on Snapshot .
Voting starts on: 29 Mar 22 18:44 UTC
Voting ends on: 05 Apr 22 18:44 UTC

1 Like