VDP-18 [Funding] Jonathan An - Towards reversing periodontal disease using Geroscience

This proposal asks for up to 300.000 USD to fund Jonathan An's research on geroscience-based treatments for periodontitis.

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 (https://doi.org/10.7554/eLife.54318.sa2) 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. (https://halo.dlmp.uw.edu/people/jonathan-an/)

Matt Kaeberlein: Professor at University of Washington. He will assess the long term healthspan and lifespan of mice after drug interventions. (https://dlmp.uw.edu/faculty/kaeberlein)

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. (https://www.seattlechildrens.org/directory/simon-c-johnson/) 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.

For more information, please see the phase 2 proposal and discussion on Discourse.