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

Longevity Working Group short report

Longevity Working Group Evaluation Team: Jason Colasanti, Estéfano Pinilla, Ariella Coler-Reilly, Sara Ramos Colmenarejo, Anonymous member

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, treating periodontal loss using this approach 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 in an 8-week study, using rapamycin as a positive control. The candidates have well established pharmacokinetics and pharmacology since they have been researched for other indications. 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. Jonathan An’s collaborators also have preliminary data showing that a few of the 5 drug 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.

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

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.
  • High feasibility: Good experimental model established within laboratory and straight-forward research plan.
  • Repurposing study: Easier transition to clinical trials.
  • Young investigator with interest to spin-out in collaboration with VitaDAO and backed by strong team.

Risks

  • Team lead lacks previous entrepreneurial experience.
  • Unclear timeline to IP.
  • The road to IP will depend on which of the 5 small molecule candidates is selected as a lead, therefore more research is needed on the current IP status of the candidates. 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. A meeting to clarify the IP strategy will be held on 2021-12-19T23:00:00Z

Outcome of the evaluation and recommendation

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

7 Likes

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.

3 Likes

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

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

3 Likes

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

3 Likes

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.

3 Likes