Reversing Periodontal Disease using Geroscience

Reversing Periodontal Disease Using Geroscience

VITADENT

Aging

Background 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. 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. Aims, Hypothesis & Results An Lab proposes to use small molecule inhibitors of the PI3K/NFkB/mTOR pathway to treat 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 (systemic administration), or (2) a direct improvement of periodontal disease, which will be tested with the second study (local administration). 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 other systemic markers of healthspan, including inflammation. The proposal is mainly based on a recent eLife paper (Rapamycin rejuvenates oral health in aging mice | eLife 7) by the research group, where they find positive effects of 8-week treatment with oral rapamycin in age-related periodontal bone loss in mice. Timeline An Lab is planning to conduct two pre-clinical studies to test the effectiveness of five selected drug candidates in reversing periodontal disease. The first study will be an 8-week study using rapamycin as a positive control. If the first study shows that any of the small molecules is effective in reversing periodontal disease to the same degree as rapamycin 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 results of these studies will provide critical pre-clinical IP data to support a future company targeting periodontal disease through geroscience. Pre-Clinical Studies ‍Required Funding: $330,000 VitaDAO Board Evaluation Writeup Periodontitis is an unmet need with great impact on healthspan. This project focusing on using a geroscience approach and alleviating inflammaging was evaluated to have strong feasibility to tackle the issue. The proposal was highly rated for a strong scientific team, high novelty and impact, as well as IP-NFT potential. The team has access to dental clinics, which would greatly accelerate the clinical trial process, if the animal studies provide positive data.

Description

Aims, Hypothesis & Results An Lab proposes to use small molecule inhibitors of the PI3K/NFkB/mTOR pathway to treat 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 (systemic administration), or (2) a direct improvement of periodontal disease, which will be tested with the second study (local administration). 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 other systemic markers of healthspan, including inflammation.

The proposal is mainly based on a recent eLife paper (Rapamycin rejuvenates oral health in aging mice | eLife 7) by the research group, where they find positive effects of 8-week treatment with oral rapamycin in age-related periodontal bone loss in mice.

Timeline An Lab is planning to conduct two pre-clinical studies to test the effectiveness of five selected drug candidates in reversing periodontal disease. The first study will be an 8-week study using rapamycin as a positive control. If the first study shows that any of the small molecules is effective in reversing periodontal disease to the same degree as rapamycin 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 results of these studies will provide critical pre-clinical IP data to support a future company targeting periodontal disease through geroscience.

Pre-Clinical Studies ‍Required Funding: $330,000

VitaDAO Board Evaluation Writeup Periodontitis is an unmet need with great impact on healthspan. This project focusing on using a geroscience approach and alleviating inflammaging was evaluated to have strong feasibility to tackle the issue. The proposal was highly rated for a strong scientific team, high novelty and impact, as well as IP-NFT potential. The team has access to dental clinics, which would greatly accelerate the clinical trial process, if the animal studies provide positive data.

Team

Owner

Owner

Owner

Owner

Owner

Organisation

University of Washington

Experiment Cost

$300,000.00

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

Project Progress

All updates

All categories

Timeline

Reversing Periodontal Disease Using Geroscience

VITADENT

Aging

Description

Pre-Clinical Studies ‍Required Funding: $330,000

Team

Owner

Owner

Owner

Owner

Owner

Organisation

University of Washington

Experiment Cost

$300,000.00

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

Project Progress

All updates

All categories

Timeline

Hypothesis formulated

Basic principles observed

Technology concept formulated

Experimental proof of concept

Technology validated in lab

Rationale

The project has conducted extensive in vivo experiments in disease-relevant aged mouse models (two independent cohorts of aged C57BL/6 mice with naturally occurring periodontal disease) demonstrating clear proof-of-concept efficacy across multiple clinically relevant endpoints: periodontal bone regeneration (confirmed by longitudinal within-animal microCT, p<0.05), reversal of gingival inflammation (NF-κB signaling, pro-inflammatory cytokines), osteoclast suppression (RANKL:OPG ratio, TRAP+ cells), and oral microbiome rejuvenation to youthful composition. Results are reproducible across two independent sites with rigorous controls and statistical significance, meeting TRL 3 criteria for early-stage efficacy in disease-relevant preclinical models with measurable, quantitative outcomes.

Assessment

High Confidence

RecommendationSUPPLEMENT

Total Score3.40

Overall Assessment

This TRL 3 project scores 3.40 out of 5.00, reflecting a moderately strong early-stage preclinical program with notable strengths and identifiable weaknesses. The project's greatest strengths lie in its therapeutic relevance (well-validated mechanism with compelling published preclinical data showing rapamycin reverses all three hallmarks of periodontal disease), favorable safety prospects (repurposed drugs with established safety profiles), and large commercial opportunity (>70% of elderly affected, no current disease-modifying therapy). The team is scientifically strong with direct domain expertise and institutional resources. The most significant weakness is the intellectual property position — no patents filed, no composition-of-matter claims possible due to the repurposing strategy, and IP limited to formulation/delivery methods that are inherently weaker and easier to circumvent. The utility of the actual candidate compounds (as opposed to the rapamycin positive control) is unproven, as the five PI3K/NFκB/mTOR inhibitors have not yet been tested in the periodontal disease model. Clinical development prospects are moderate given the early stage and lack of a defined regulatory strategy. Overall, this is a scientifically well-founded project with a clear unmet medical need and strong proof-of-concept for the pathway, but it faces meaningful IP and candidate validation risks that must be addressed as it progresses. The project would benefit from: (1) completing the planned 5-compound preclinical study to validate candidates beyond rapamycin, (2) filing provisional patents on delivery/formulation innovations as early as possible, (3) developing a clearer regulatory and clinical development roadmap, and (4) adding translational/commercial expertise to the team.

Weighted Score

Therapeutic Relevance

Strong therapeutic relevance: the PI3K/NFκB/mTOR inflammaging mechanism is well-validated in the published eLife study, demonstrating reversal of all three clinical hallmarks of periodontal disease (bone loss, inflammation, microbiome dysbiosis) in aged mice with rapamycin. The geroscience hypothesis is compelling and supported by robust preclinical data across two independent cohorts (NIA-UW and JAX). However, the five new candidate compounds have NOT yet been tested in this disease context, so the mechanistic validation applies primarily to rapamycin (positive control) rather than the novel candidates. Score of 4 rather than 5 because the extension from rapamycin to the broader PI3K/NFκB/mTOR inhibitor class remains unproven.

Therapeutic Optionality

Good optionality beyond the primary periodontal disease indication. Secondary indications include peri-implantitis (large market), cognitive decline/neurodegeneration (collaborator has preliminary data), and broader healthspan/lifespan extension. The study design captures cognitive function and lifespan endpoints in the same animals, enabling efficient exploration of multiple therapeutic areas. The geroscience approach inherently supports multi-indication potential. Docked one point because these secondary indications are speculative at this stage with no dedicated preclinical data yet generated for this project's specific compounds.

Intellectual Property

This is a significant weakness. No patents have been filed yet; IP generation is contingent on successful preclinical outcomes. The drug repurposing strategy means composition-of-matter patents are not available — IP would be limited to methods of use, formulation, and delivery claims (toothpaste, trays, periodontal pocket delivery), which are generally weaker and easier to design around. The VDP-18 evaluation and project documents both explicitly flag this as a risk. Freedom-to-operate analysis is incomplete (no blocking patents identified, but no formal FTO conducted). Product development will require partnerships. The IP position is inherently constrained by the repurposing approach.

Utility Of Candidates

Mixed picture. Rapamycin (positive control) has strong demonstrated efficacy in the disease model — actual new bone growth, reduced RANKL/OPG ratio, reduced TRAP+ osteoclasts, reversed NF-κB signaling, restored youthful microbiome composition, all with statistical significance across two independent cohorts. However, the five novel PI3K/NFκB/mTOR candidate compounds that are the actual focus of this project have NOT been tested in periodontal disease models yet. Their PK/PD profiles are established from other indications (repurposing), which de-risks somewhat, but there is no direct efficacy data for these candidates in the target indication. The project is essentially at the stage of proposing to test candidates rather than having demonstrated their utility. Score of 3 reflects strong proof-of-concept for the pathway but unproven candidates.

Prospects For Safety

Favorable safety profile expected. Rapamycin is FDA-approved with well-characterized safety/toxicity data. The candidate compounds are existing drugs with established pharmacokinetics and pharmacology from other indications, significantly de-risking safety concerns. The 8-week treatment duration is short-term, reducing chronic exposure risks. The local delivery sub-study (gum-line application) could further minimize systemic exposure and associated side effects. However, rapamycin does have known immunosuppressive effects, and the safety of the five specific candidate compounds in the oral/periodontal context has not been evaluated. No formal toxicology studies have been conducted for this specific application. Score of 4 reflects the strong baseline safety knowledge from repurposing but acknowledges gaps in indication-specific safety data.

Prospects For Gmp Cmc

Drug repurposing strategy is advantageous for GMP/CMC. The candidate compounds are existing small molecules with established manufacturing processes from other indications. Rapamycin is already commercially manufactured at scale. The encapsulated rapamycin (eRAPA) formulation used in preclinical studies is available from Rapamycin Holdings. Novel formulations (toothpaste, trays, periodontal pocket delivery) would require development but are based on well-understood delivery technologies. No significant manufacturing challenges are anticipated for the active pharmaceutical ingredients themselves. Score of 4 rather than 5 because the novel delivery formulations (local delivery systems) have not been developed or tested yet.

Prospects For Clinical Development

Moderate prospects. Positive factors: rapamycin is FDA-approved (facilitating regulatory pathway), the PI has direct access to a dental clinic for future human studies, periodontal disease has well-established clinical endpoints (bone loss measurement, inflammation markers), and the repurposing approach simplifies the regulatory path. However, significant gaps remain: the five candidate compounds have not yet been tested in the disease model, no IND-enabling studies have been planned, no regulatory strategy has been articulated, and the path from mouse to human clinical trials is not well-defined. The project is still at early preclinical stage with planned (not completed) animal studies for the actual candidates. Non-human primate studies are mentioned but not planned in detail. Clinical development is likely several years away.

Commercial Potential

Large addressable market: >70% of older adults affected by periodontal disease, representing a major global unmet medical need. Current treatments are invasive, repetitive, and symptom-focused — a non-surgical medical therapy would be highly differentiated. Multiple commercial formats possible (prescription toothpaste, OTC products, periodontal pocket delivery). Secondary markets in peri-implantitis and potentially cognitive health. However, weak IP position (no composition-of-matter patents) limits commercial defensibility. The VDP-18 evaluators scored Market Advantage as Strong/Satisfactory (mixed). Product development requires partnerships. Score of 4 reflects the enormous market opportunity tempered by IP-related commercial risks.

Organization And Team Fit

Strong scientific team. PI Jonathan An has direct expertise in periodontal biology and geroscience, with a published track record in this exact research area (eLife paper). Matt Kaeberlein is a prominent aging researcher providing healthspan/lifespan expertise. Simon Johnson adds neurodegeneration and cognition assessment capabilities. The team is based at University of Washington with access to necessary infrastructure (animal facilities, microCT, dental clinic). However, the PI lacks entrepreneurial experience (noted as a risk), and the team may need additional expertise in drug development, regulatory affairs, and commercialization for later stages. VDP-18 evaluators scored Science Team as Strong/Outstanding. Score of 4 reflects excellent scientific credentials with gaps in translational/commercial experience.