Mr. Chairman and Members of the Committee: I am pleased to present the President’s Fiscal Year (FY) 2019 budget request for the National Institute of Dental and Craniofacial Research (NIDCR) of the National Institutes of Health (NIH).
The mission of NIDCR is to improve dental, oral, and craniofacial health through research, research training, and the dissemination of health information. A recent study looking at personal healthcare spending in the United States by condition estimates that Americans spend $66.4 billion annually on the treatment of oral disorders and another $48.7 billion for general dental care and preventive services. Together, the total surpasses the costs of treatment related to a common condition among Americans – diabetes – by more than $13 billion[1]. NIDCR leads the effort to reduce this burden by supporting basic, translational, and clinical research and research training to improve dental, oral, and craniofacial health. By promoting the timely translation of those findings into practice NIDCR helps advance treatment and prevention strategies for all Americans.
To prioritize emerging areas of scientific inquiry that are ripe for significant advances over the next decade, we launched a long-term strategic initiative called NIDCR 2030. As part of this bold, forward-looking plan, NIDCR will support research that integrates oral health into overall health and uncovers the common risk factors and underlying biological mechanisms of health and disease throughout the body. This knowledge will inform the development of new preventative and therapeutic interventions to improve dental, oral, and craniofacial health – as well as the health of the whole body.
PIONEERING A GENE THERAPY TO TREAT CHRONIC DRY MOUTH
For most people who survive head and neck cancers, successful treatment with radiation therapy comes at a high price – significant loss of salivary gland function, leading to chronic dry mouth and its adverse health effects. Radiation therapy works by killing malignant tumor cells, but it does not discriminate among cell types. It also kills saliva-producing cells, which causes saliva production to shut down. This can lead to problems chewing, tasting, talking, and swallowing food, and significantly increases the risks for dental decay, tooth loss, and oral infections. NIDCR supports research to unravel the complex molecular and cellular processes involved in salivary gland function and fluid secretion. These investments have inspired the development of a gene therapy to treat chronic dry mouth caused by radiation treatment. The therapy delivers specific DNA sequences into the surviving salivary gland cells, resulting in the production of specialized tube-shaped proteins called aquaporins, which allow water to flow out of the salivary gland cells. Studies in mouse models showed that the gene therapy generated enough aquaporin proteins to restore salivary flow. This research led to a clinical trial conducted on the NIH campus that is currently recruiting patients to test the gene therapy treatment in people whose salivary glands have been damaged by radiation therapy for head and neck cancer. Results from the first phase of the study are encouraging and suggest that this approach could be a promising treatment. Building on these studies, another clinical trial is being planned to see if the therapy can also be used to restore salivary function in individuals whose chronic dry mouth is caused by Sjögren’s syndrome, an autoimmune disorder that damages salivary glands.
DEVELOPING INNOVATIVE TECHNIQUES TO ADVANCE REGENERATIVE MEDICINE
A major priority for NIDCR is advancing regenerative medicine research to improve the lives of those with dental, oral, and craniofacial conditions or diseases. A significant challenge in regenerating load-bearing tissues such as joint cartilage is engineering and growing tissues that are as strong and flexible as the body’s natural ones. The cartilage that makes up joints, such as the temporomandibular joint in the jaw, must be extremely resilient to withstand a lifetime of repetitive movement and mechanical stress. To overcome this obstacle, NIDCR-supported scientists are developing techniques to generate functional tissues in the laboratory for regenerative medicine therapies. These scientists developed a device that physically pulls on single layers of cartilage cells while they are being grown on a flat, supportive matrix, resulting in tissues with strength and elasticity that more closely resembles natural cartilage. Using this technique results in engineered cartilage that is more resilient to wear and tear, making it especially useful as a potential replacement for damaged cartilage in highly mobile joints. Future uses could include the development of better treatment options for temporomandibular joint and muscle disorders (TMD) and joints damaged by osteoarthritis. Further development of this novel cartilage growth technique, and its expansion to other cell types could open the door to exciting possibilities for the engineering and generation of more durable and flexible tissues for use throughout the body.
FINDING PAIN RELIEF IN UNEXPECTED PLACES
Chronic pain is a major health problem that affects almost one-quarter of the US population[2]. Opioids are often prescribed to alleviate chronic pain, although they carry a strong risk for addiction. Identifying new effective and non-addictive pain treatments remains a priority for NIDCR, especially in regard to TMD, a group of conditions that can cause severe and chronic pain in the jaw and muscles of the head and neck. In 2005, NIDCR launched OPPERA (Orofacial Pain, Prospective Evaluation and Risk Assessment) – a multi-site population-based study – to identify the biopsychosocial and genetic risk factors that cause TMD. Early OPPERA studies found an association between the gene for epidermal growth factor (EGFR) and the development of chronic pain in patients with TMD. Drugs that block the activity of EGFR are currently being used to inhibit tumor growth in some types of cancer. Strikingly, there have been case reports of cancer patients reporting a significant reduction in pain when treated with EGFR-blocking drugs. Taking these observations into the laboratory, NIDCR-funded investigators used a mouse model to show that EGFR-blocking drugs alleviate inflammatory and neuropathic pain. These drugs function by blocking the activity of EGFR in neurons that receive and interpret sensory stimuli – such as pain – in the body. This intriguing finding could lead to the development of more effective treatments for chronic pain that also reduce the risks for addiction.
ADVANCING TREATMENTS FOR HPV-POSITIVE AND HPV-NEGATIVE OROPHARYNGEAL CANCERS
Oropharyngeal cancers form in the middle part of the throat, including the back of the mouth, base of the tongue, and the tonsils, and are often caused by HPV (human papilloma virus), the same virus that causes cervical cancer. These cancers are known as HPV-positive (HPV+) oropharyngeal cancers. Experts estimate that 60 to 70 percent of newly diagnosed oropharyngeal cancers in the United States are likely to be HPV+, especially among young men and women. Although people exposed to the HPV virus are more likely to develop oropharyngeal cancer, paradoxically, HPV+ cancers respond much more successfully to chemotherapy than HPV-negative (HPV-) cancers. A collaboration of clinicians and basic science researchers funded by NIDCR are studying the biomolecular reasons for this difference in treatment outcomes to see if there is a way to separate out the HPV+ beneficial response to treatment and then apply it to HPV-negative (HPV-) oropharyngeal cancers. To do this they looked closely at the activities of cisplatin – the most commonly used chemotherapy for many cancers – which is better at killing HPV+ cancer cells than HPV- cancer cells. The team discovered an HPV protein called E7 that enhances the effectiveness of cisplatin treatment, and then developed a small protein fragment (peptide) called E2F5 that mimics the HPV protein E7 without the HPV infection. Combining this novel peptide with cisplatin treatment in HPV-negative patients led to improved outcomes, similar to those of HPV+ patients. Next steps will be to clear the FDA requirements for producing the E2F5 peptide and establishing treatment protocols for clinical trials.
REFERENCES
[1]Dieleman J. US Spending on Personal Health Care and Public Health, 1996-2013. JAMA. 2016; 316(24):2627-2646.