New Study Funded: Towards reversing periodontal disease using Rapamycin

[RapAdmin]

Great news for the University of Washington Research Team being led by the usual suspects, Jonathan An, Matt Kaeberlein et al.

$300,000 in funding from VitaDao for this new research project which looks at the potential for rapamycin and other small molecules (I suspect other mTOR inhibitors like everolimus, etc.) to treat and reverse periodontal disease. And if all goes well, as I expect it will, we’ll all be using Rapamycin toothpaste soon…

Come to think of it, we may need an entirely new, larger bathroom cabinet for the rapamycin skin cream to slow skin aging, rapamycin shampoo for hair follicle aging, hair loss/color restoration, and now rapamycin toothpaste.

The idea for this current study came from last year’s successful research in this area, as covered in this post: New Study: Rapamycin Rejuvenates Oral Health in Aging Mice.

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: Compound 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.

Full Project Details here: VDP-18 [Funding] Jonathan An - Towards reversing periodontal disease using Geroscience

[EnrQay]

This is much like the delivery system of fluoride. Rapamycin dental floss to get deep in the pockets? Mouthwash? Concentrated dentist office treatments?

[MAC]

With regards to Alzheimers disease (classic amyloid plaque defined dementia), there is a theory that amyloid isan anti-microbial peptide in response to microbe induced inflammation, and oral microbes are a major source. As of 2022, the scientific community still does not understand the APP (Amyloid Precursor Protein)/Amyloid Plaque functions in humans!

There have been many studies in various animal models (especially human transgenic AD expressing and/or APOE4 expressing) that show strong improvement in cognition with Rapamycin treatment.

So any Rapamycin study that perhaps captures cognitive as a primary/secondary endpoint would further this pathway validation.

Periodontal disease is associated with cognitive dysfunction in aging dogs: A...

The antimicrobial protection hypothesis of Alzheimer's disease - PubMed

Targeting Infectious Agents as a Therapeutic Strategy in Alzheimer's Disease...

β-Amyloid is an Immunopeptide and Alzheimer's is an Autoimmune Disease - PubMed

[RapAdmin]

So - my question to everyone here is, who’s going to be first to make their own Rapamycin toothpaste and try this out and report back?

[MAC]

Sounds like a very tricky endeavour vs systemic delivery to oral tissues.

What’s vehicle for the Rapamycin? Surely not toothpaste…is there any absorption?

And how long to expose the gums?

Not to mention the wastefulness of all that Rapamycin going down the drain on delivery/rinse.

I also wonder about canker mouth sores with very high topical concentration of Rapamycin, although I think they derive from systemic exposure.

I mean it’s possible, but would require some CRESTAMYCIN development.

[Jared]

You’d want to treat this disease systemically. Periodontitis is an inflammatory disease of the alveolar bone. It occurs in areas that can’t be reached easily with at home care products. This is why your hygienist digs deep beneath the gum line.

[EnrQay]

@RapAdmin

So - my question to everyone here is, who’s going to be first to make their own Rapamycin toothpaste and try this out and report back?

Me. I’m going to mix up a small batch at 0.01%. I picked this percentage based on the higher level in Dr. Green’s skin recipe of about 0.016%. Since we are talking about mucus membranes in the mouth, I figure absorption would be better, so lower the %. If I am doing my math right today, a 3.5oz (almost 100,000mg) tube of toothpaste would need 10mg rapamycin

[alextrent]

To Jared’s comment…Yes and no. if you have severe disease need to get it scraped first. That is traditional therapy…have had it done twice…painful and expensive and the current consensus is really does not work without other adjunct therapy. Systemic antibiotic treatment post-op works and should be done or the cleaning wounds get back to where they were. May need to be long term.

However in mild cases topical therapy works. In my case worked better than the surgery. Chlorhexidine works but over long term stains the teeth. Hyaluronic acid is great. I use it and it works. Use the cosmetic product. It does not stick very well but is viscous so does hang around long enough. come in a gal as well but I cannot find it recently.

Generally the gum problems are right below the gumline and there are pockets, to the topical stuff get in. A Rapa product would be great.

[alextrent]

On making one’s own gum treatment. I don’t think you need the toothpaste and certainly no “brushing”. Just massage the skin creme into the gumline. That is the way the current topicals are applied and they work.

[Joseph]

FWIW…

From;
https://www.sigmaaldrich.com › deepweb › assets › sigmaaldrich › product › documents › 289 › 717 › r0395pis.pdf

Rapamycin can dissolve in chloroform ( 5 mg/ml),² in methanol (25 mg/ml)², and in DMSO (25 mg/ml)².

Used DMSO as the solvent and carrier, will transport through cell membranes.

r0395pis.pdf (59.3 KB)

[chrisb]

It would seem most of us are ingesting it systemically already, right? My use of rapa (20mg every two weeks) began approx. The same time I was diagnosed with early stage periodontal disease. I was super stoked to read the studies, and have not had bleeding gums or other symptoms since starting. Dental care can be so expensive in the USA that this can only be a good thing and I look forward to my next exam to see if it actually is helping.

[RapAdmin]

Yes - I think virtually everyone here has been focused on ingesting the rapamycin orally. It would seem, however, to be potentially beneficial to do both - oral, and topically inside the mouth via some sort of rapamycin toothpaste, mouthwash, floss, etc.

[RapAdmin]

@KERRY_BELL posted this in another forum, and I thought people here would like to see it:

Im 75 yo., and my gums have not receeded which is usually what happens when your get older. They are no different than when I was 30. Of course, brushing, flossing and Rapamycin weekly. I truly believe rapa has helped.

[been taking rapamycin for] 5 years, March 2017. Dr. Greens 2nd. patient.

[RapAdmin]

@Joseph

Used DMSO as the solvent and carrier, will transport through cell membranes.

Wouldn’t transcutol still be the best agent to dissolve the rapamycin in?

I have transcutol, and used it with to make the rapamycin skin cream I tried for 6 months (minor improvement, not sure if its worth it), but it also seems like it could be used for topical application on the inside of the mouth.

Does anyone here have experience with DSMO? I’ve not tried it, but have heard that it may have some unenjoyable smell or something like that.

Transcutol HP - Pharma Excipients

[Joseph]

DMSO The perfect solvent.
It will carry any compound dissolved through skin into blood stream and or into cells.

DMSO (a.k.a. dimethylsulfoxide) - The Anti-Aging Medical Clinic

[RapAdmin]

Joseph - have you used DSMO before? What for, and are there any downsides from what you’ve heard?

[Joseph]

Yes, both topical and intravenous.

Attached is a gift.

Dimethyl Sulfoxide (DMSO) in Trauma and Disease

dimethyl-sulfoxide-dmso-in-trauma-and-disease-2015 (1).pdf (3.6 MB)

[Jared]

Perio disease will be evaluated 2 ways. Radiographically (x-rays) and clinically (probing depths). A reduction in pocket depth would be a start and then the arrest of bone loss would be the other. I doubt we’d see any regeneration of alveolar bone but sometimes magical things happen.

[RapAdmin]

@Jared

I doubt we’d see any regeneration of alveolar bone

Didn’t we see bone regeneration here, in this past study with rapamycin?

New Study: Rapamycin Rejuvenates Oral Health in Aging Mice

[Screen Shot 2021-10-13 at 12.26.49 PM] Dr. Jonathan An and Dr. Matt Kaeberlein of the School of Dentistry, along with their colleagues across the country, have found that rapamycin can regenerate bone and decrease gum inflammation, pointing the way toward new treatments for common dental problems in aging patients. Using a 3-D imaging technique called microcomputed tomography, the researchers measured the periodontal bone of the rapamycin-treated and untreated mice. The treated mice had more bone than the untreated mice and had actually grown new bone during the period they were receiving rapamycin. In their studies of rapamycin in old mice, the researchers found another intriguing effect: The drug significantly changed the oral microbiome, which is the mouth’s bacterial population. T…

[Jared]

Recession isn’t always perio disease related. In fact it’s usually a result of bruxism. In perio disease you don’t usually get recession of the gums, just recession of the bone which then results in increased pocket depths.