Whether we are ready or not, our future will be shaped by an overabundance of data and ever-smarter technologies to make sense of those data. In medicine, analyses of explosive amounts of genomic data have illuminated our understanding of the genetic and epigenetic basis of diseases - most notably cancer - and have led to the advent of precision medicine. The National Cancer Institute defines precision medicine as “a form of medicine that uses information about a person’s own genes or proteins to prevent, diagnose, or treat disease (1).”
In 2015, President Obama launched the Precision Medicine Initiative which invested $215 million to research developing novel tools and targeted therapies with the vision of “empower[ing] patients, researchers, and providers to work together toward development of individualized care (2).” Precision medicine is here, and it has been well underway in accelerating healthcare transformation. The question is, where does dentistry stand in the precision medicine revolution?
Possible Applications of Precision Medicine in Dentistry
The quick answer is that application of precision medicine to dentistry is still very much in its infancy. Dentistry, however, holds unique potential for advancing and benefiting from precision medicine, and two key areas that seem to hold the most promise for the realization of personalized medicine in dentistry are Periodontology and Cariology.
Periodontal Disease
Wide use of individualized treatment for periodontitis based on genetic tests may become a reality sooner than one might imagine. Periodontitis has a close association with a number of systemic conditions ranging from diabetes and atherosclerosis to congenital syndromes such as the Papillon-Lefevre Syndrome. Subsequently, genetics can influence individual risk for periodontal disease by affecting the structural integrity of periodontium and host immune reaction to subgingival bacterial invasion.
It is estimated that the heritability of genetic control of periodontal disease can be as high as 50% (6), and one of the cytokines that interacts with oral microbiome to cause periodontitis is IL-1, which plays a key role in the inflammatory response. Mice studies found that the presence of certain variants of the IL-1 gene family leads to a higher incidence and severity of periodontitis (3)(4).
Based on these findings, there is an ongoing effort to develop a reliable genetic susceptibility test for periodontal diseases. PerioPredict, made commercially available in January 2014, is a genetic susceptibility test that tests for IL-1 gene variants, which allows clinicians to risk-stratify patients and come up with individualized treatment (5). For instance, those who are identified as high risk for periodontitis based on PerioPredict results can receive two to three prophylaxis per year while those who are at less risk can receive one prophylaxis per year.
Dental Caries
There has been growing literature investigating the genetic control of caries susceptibility, which makes dental caries another possible oral disease that can benefit from precision medicine. For instance, research studies have identified a number of genes that are consistently associated with high risk for caries: the AMELX gene involved in enamel development, KLK4 gene involved in enamel maturation, CA6 gene involved in saliva pH regulation, LYZL2 gene involved in antibacterial defenses, etc(3)(6).
While genetics certainly plays a role, estimation of the heritability of caries varies widely from 20% to 85%, which underscores the predominant role of personal and environmental factors in disease progression in caries (6). Host and environmental factors such as oral hygiene practices, diet, material health, and socioeconomic status play a key role in the extent to which genetic susceptibility translates into caries experience. Establishing a direct relationship between genetic markers and dental caries has been met with more challenges compared to one for periodontal diseases, and there are currently no available genetic tests in the market that reliably test for caries susceptibility.
Although predicting caries risk based on genetics may not yet be realizable, advancements in the field of regenerative dentistry may allow for a biological approach to treating deep cavities. In deep lesions involving pulp exposure, dentin is able to stimulate dental pulp stem cells to differentiate into odontoblast-like cells which produce reparative dentin. Based on this natural process, several therapies are already being developed, many of which are entering clinical trials soon (9). For instance, one study by researchers at King’s College London demonstrated how small molecule GSK3 (glycogen synthase kinase 3) antagonists can be delivered on collagen sponges to promote reparative dentin formation (8). In the near future, such findings can be translated into a novel therapy for treating dentinal cavities.
Other possible areas
Orthodontics and oral oncology are two additional areas that may hold promise for individualized oral health therapy in the future. There has been an enormous research effort to understand epigenetic mechanisms of oral cancer and to identify reliable biomarkers for oral cancer to develop an effective oral cancer screening device. While a number of oral cancer diagnostic tools have been introduced to the market, there are many limitations that remain to be addressed.
Orthodontic studies have found genes implicated in class III malocclusion, or mandibular prognathism, which include those that encode certain growth factors such as Indian hedgehog homolog and parathyroid-hormone-like hormone (3). There is also robust research on the genetic mechanisms underlying craniofacial abnormalities like cleft lip and palate. With these understandings, personalized orthodontic treatments may be possible in the future.
Potential for Growth
While these aforementioned areas are certainly promising developments, there is still much work to be done to integrate personalized medicine in dentistry. ADA, in reviewing the literature on genetics and oral health, concludes that “while genetic testing holds potential for clinical application in the future, clinical measurements remain the best approach for assessment of caries and periodontal disease at this time (6).”
On a positive note, however, several aspects of dentistry present special opportunities for integration of precision medicine into clinical practice. Routine nature of dental visits and long-term relationships that dentists have with their patients are unique advantages that allow for easy access to biomarkers drawn from saliva and other constituents of oral cavity and chairside administration of personalized therapies. For instance, with the growing understanding of the role of oral microbiome in oral and systemic health condition, microbiome-based diagnostics and therapeutics may be developed in the future to both monitor and manipulate oral microbiome with the goal of maintaining oral health (7).
As the transformation of healthcare from an interventional model focused on chronic disease management to a prevention and health promotion-centered model continues, it is critical that we as future oral health care professionals develop the necessary skills to assess new therapeutic tools and make informed clinical decisions to provide optimal care for our patients.
References
Dictionary of Cancer Terms.” National Cancer Institute, www.cancer.gov/publications/dictionaries/cancer-terms/def/precision-medicine.
“White House Precision Medicine Initiative.” National Archives and Records Administration, National Archives and Records Administration, obamawhitehouse.archives.gov/precision-medicine.
Reddy, Manchala Sesha et al. “Embracing Personalized Medicine in Dentistry.” Journal of pharmacy & bioallied sciences vol. 11, Suppl 2 (2019): S92-S96. doi:10.4103/JPBS.JPBS_297_18
Grigoriadou, Marianna E et al. “Interleukin-1 as a genetic marker for periodontitis: review of the literature.” Quintessence international (Berlin, Germany: 1985) vol. 41,6 (2010): 517-25.
“PerioPredict Genetic Risk Test - Tests - GTR - NCBI.” National Center for Biotechnology Information, U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/gtr/tests/509242.1/.
“Oral Health Topics: Genetics and Oral Health.” Genetics and Oral Health, www.ada.org/en/member-center/oral-health-topics/genetics-and-oral-health.
Willis, Jesse R, and Toni Gabaldón. “The Human Oral Microbiome in Health and Disease: From Sequences to Ecosystems.” Microorganisms vol. 8,2 308. 23 Feb. 2020, doi:10.3390/microorganisms8020308
Neves, Vitor C. M., et al. “Promotion of Natural Tooth Repair by Small Molecule GSK3 Antagonists.” Nature News, Nature Publishing Group, 9 Jan. 2017, www.nature.com/articles/srep39654.
Sharpe, Paul. “Regenerative Dentistry.” Frontiers in Dental Medicine, vol. 1, 2020, doi:10.3389/fdmed.2020.00003.
https://www.pearsallcreative.com/periopredict
תגובות