Mr. Chairman and Members of the Committee:
I am pleased to present the President's budget request for the
National Institute of Dental and Craniofacial Research (NIDCR) for
Fiscal Year (FY) 2005. The FY 2005 budget includes $394,080,000, an
increase of $11,032,000 over the FY 2004 level of $383,048,000
comparable for transfers proposed in the President's Request.
DELIVERING ON THE PROMISE OF BASIC RESEARCH
Although highly technical in nature, basic research provides the
detailed molecular clues that scientists and clinicians can use to
develop new strategies that more effectively prevent or treat disease.
This year, I would like to highlight how NIDCR's investment in the
basic sciences continues to yield important advances in oral and public
health. I also would like to mention how NIDCR stands to benefit from
the recently launched NIH Roadmap which has the potential to catalyze
virtually all areas of oral health research and, most importantly,
hasten the development of novel treatments that could greatly improve
American oral health.
GENE TRANSFER AND THE SALIVARY GLANDS
A prime example of basic research creating new clinical
opportunities is the transfer of replacement genes into the salivary
glands for therapeutic purposes. In the early 1990s, a team of NIDCR
scientists published their initial paper on the technical feasibility
of this approach. Thereafter, they began a unique long-term research
interest in transferring replacement genes into the salivary glands of
persons with Sjögren's syndrome and cancer patients whose salivary
glands were damaged during radiation treatment. The hope was that the
replacement genes would increase the production of saliva and eliminate
the chronic parched sensation that plagues people with dry mouth
conditions.
The NIDCR scientists also began to apply their gene transfer studies
to a third and seemingly less obvious therapeutic area: single-protein
disorders, such as type I diabetes, human growth hormone deficiency,
and erythropoietin-responsive deficiencies. Frequently overlooked in
the medical literature, salivary glands not only release saliva into
the mouth, they routinely secrete digestive enzymes and other proteins
into the circulatory system. As the scientists later would demonstrate,
the salivary glands readily accept gene-carrying vehicles, or vectors.
Thereafter, with minimal coaxing, the salivary glands act as natural
protein factories, dutifully manufacturing the encoded replacement
protein and pumping it at steady levels into the circulation. The
approach has some built in advantages over gene therapy in other parts
of the body, such as the liver. Salivary glands are easily accessible
and any potential adverse effects would be non-life threatening.
Moreover, salivary gland cells are encapsulated to prevent leakage of
the vector into the circulation and to other tissues.
Recently, the group developed a new version of gene-carrying vector
that entered the salivary glands of mice and produced the human protein
erythropoietin for at least one year, a major step forward in the
research. Just as importantly, the vector - a stripped down,
bioengineered version of the harmless adeno-associated virus - did not
trigger a sustained immune response, a common setback in gene therapy
experiments.
Building on this strong basic research base, NIDCR has developed a
new initiative to evaluate the safety and efficacy of salivary gland
gene transfer techniques in people with systemic single-protein
deficiencies. The initiative will consist of three Phase I/II clinical
trials. The first clinical trial will involve a prototype systemic
single-protein deficiency disorder, adult growth hormone deficiency. As
currently proposed, 21 patients will be enrolled in the study, which
will be completed in four years. If successful, a second clinical trial
will be conducted to treat people with erythropoietin-responsive
deficiencies and ultimately a third clinical trial for those with
Sjögren's syndrome and/or cancer patients with dry mouth.
PERIODONTAL DISEASE AND PRETERM BIRTH
Another outstanding example of basic research creating new clinical
opportunities is in the area of preterm pregnancy. In the United
States, about one in eight babies is born prematurely i ,
which is defined as a birth that occurs three or more weeks earlier
than the expected due date. As all too many parents have tragically
experienced, extremely preterm babies can be so small and
underdeveloped that they must remain hospitalized for months and, if
they survive, spend years battling chronic health problems.
This serious and common problem has spurred scientists to identify
"risk factors" associated with premature births. These risk factors -
which now include smoking, low-income status, hypertension, diabetes,
alcohol use, genitourinary tract infections - allow doctors to identify
women who are more likely to deliver prematurely and thereby tailor
their prenatal care to control or eliminate the risk factors.
However, the list of risk factors remains a work in progress. An
estimated one in four preterm births occur without any known
explanation, and that has left scientists searching for additional
susceptibility factors to help more mothers and reduce the estimated
$13.6 billion per year spent in the United States on hospital stays for
infants with a diagnosis of prematurity.ii
In the mid 1980s, scientists began to suspect that periodontal
disease might be one of these elusive risk factors. These NIDCR
grantees and colleagues monitored women with more serious periodontal
disease and found they were more likely to deliver early than those
with mild or non-existent disease. They also have developed a plausible
biological explanation to explain the possible association. Based on
animal studies, the scientists hypothesized that certain bacteria from
severe periodontal infections, most notably Porphyroma gingivalis ,
enter the bloodstream and eventually circulate to the womb. There, the
oral pathogens colonize and irritate the uterine wall. This causes
inflammation of the uterus and a rise in prostaglandins and other
infection-signaling chemicals, which can induce early contractions and
trigger premature labor.
Left unanswered is whether treating women for periodontal disease
during pregnancy will help them give birth to full term babies. The
NIDCR recently launched two large randomized clinical trials to answer
this important public health question. These national studies, which
merge the disciplines of dentistry and obstetrics, will involve over
2,600 women of various racial, ethnic, and economic backgrounds. What
is unique about these clinical trials is there will be a yes-or-no
outcome for each woman within 37 to 40 weeks, or the completion of the
pregnancy. Women will not need to be tracked at great expense for 10 or
20 years to get the final answer, as is often the case in clinical
research. Once all the data are compiled and analyzed, which could take
an estimated five years to assemble and analyze, researchers anticipate
that they will have sufficient clinical data to offer sound scientific
advice one way or the other on this critical public health issue.
PAIN RESEARCH
In another example of the potential payoff from basic research,
scientists are mapping in greater detail the multiple routes, or
pathways, that sensory signals travel en route to the spinal cord and
brain. This work has resulted in several new leads in how to more
effectively manage pain. One of the most promising new leads stems from
work conducted at the NIDCR. Our scientists found that an ultrapotent
compound selectively eliminated an entire class of pain-sensing neurons
from the peripheral nervous system of a living organism. The compound,
called resiniferatoxin (RTX), killed the neurons, blocking inflammatory
pain, thermal pain sensation, and reducing hypersensitivity to pain.
Importantly, the animals maintained their ability to sense pain, in
this case from a pinch, and they remained well coordinated, an
indication that RTX did not affect sensory nerves in the muscles and
joints. Since these initial reports, the investigators have assembled
additional preclinical data and are moving rapidly toward evaluating
RTX in human clinical trials.
In order to seed additional discoveries in pain research and to help
more Americans effectively manage pain, the NIDCR will begin an
initiative to define the proteins and protein networks involved in
processing pain-signal information in the orofacial region. This
initiative encourages interdisciplinary studies that employ genomic and
proteomic approaches, imaging technology, and computational biology to
clarify the molecular events involved in chronic orofacial pain
disorders.
PUTTING RESEARCH INTO PRACTICE
To achieve our goal of improved oral health for all people, NIDCR
must ensure that research advances are translated and adopted into
clinical practice. Many of the unique questions faced by dental health
professionals on a daily basis are most appropriately addressed in
dental practice settings, among unselected patient populations.
Practice based research networks can generate important and timely
information to guide the delivery of health care and improve patient
outcomes. The NIDCR will launch an initiative to create dental Practice
Based Research Networks (PBRNs) to conduct clinical research. In time,
linking the oral health practice based research networks with existing
medical networks will provide additional patients, professional
expertise, and integration of resources for conducting research across
a broad spectrum of health care specialties. By connecting
practitioners with experienced clinical investigators, PBRNs will
enhance clinical research supported by the NIDCR and produce findings
that are immediately relevant to practitioners and their patients. The
networks can support a variety of clinical studies with clear and
easily defined outcome measures, and they typically draw on the
experience and insight of practicing clinicians to help identify and
frame the questions. Because research is conducted in the real world
environment of dental practice, the results are more likely to be
readily adopted by practitioners.
NIH ROADMAP
The NIH Roadmap provides several additional opportunities to the
oral-health research community. For example - the goals of the
initiative Building Blocks, Biological Pathways and Networks -
are closely linked to NIDCR's molecular anatomy efforts to identify the
full complement of genes, proteins and protein networks that are
expressed in both oral cancer and periodontal disease. Advances in
proteomic analysis platforms will be crucial for NIDCR to achieve its
goal of defining the salivary proteome - a critical step in the
Institute's long-term goal to exploit the salivary secretions for
diagnostic purposes. The Molecular Libraries and Molecular Imaging initiative
holds great promise for accelerating NIDCR's progress in defining the
molecular pathways of pain reception and in elucidating new therapeutic
targets to manage chronic pain. In addition, the initiative Research Teams of the Future will
enable NIDCR's ongoing inter- and multidisciplinary efforts to further
expand and develop new ways to approach research questions. Finally,
the integration of dentists into the new clinical research
infrastructure that will be created by the Roadmap is key given that
overall health and oral health are interrelated and that certain
systemic conditions such as diabetes, Sjögren's syndrome, HIV/AIDS and
osteoporosis have important oral symptoms, manifestations or
complications.
NIDCR envisions a clear path ahead for oral and craniofacial
research. Many exciting new leads that have been reported in recent
years makes it easy to imagine that the next wave of research advances
will have a more profound and far reaching effect on oral health than
ever before.
i March of Dimes Birth Defects Foundation. http://peristats.modimes.org . Accessed on March 15, 2003 .
ii March of Dimes, PeriStats.