I recently presented at Spotlight Health 2016, the health-focused portion of the Aspen Ideas Festival, about how studying and treating rare diseases can inform innovative treatment approaches for more common medical conditions. Our Division of Genetics and Metabolism sees more than 8,000 patients a year with rare conditions, such as urea cycle disorders and Down syndrome. Through decades of analyzing these diseases and treating children who have them, we have developed therapies that apply not only for the small numbers of patients who have rare diseases but also for more common conditions caused by environmental factors leading to a similar physical response.
For instance, we’ve demonstrated that the stress of cardiopulmonary bypass during surgery to correct congenital heart disease creates conditions similar to a critical blockage in the urea cycle, specifically the biochemical creation of citrulline, a key biochemical.
When that cycle is unable to flow, or continuing the river analogy, becomes dammed up due to a genetic defect, as in urea cycle disorders, or an environmental factor, such as the extreme stress of cardiopulmonary bypass, the body is unable to make enough citrulline which is critical for maintaining normal blood pressure. We’ve shown that replacing that citrulline can correct a lot of these problems whether caused by rare genetics or the cardiac OR.
Applying rare disease treatment approaches to more common diseases is not limited to urea cycle disorders. Work by my colleague Carlos Ferreira, MD, demonstrates how a rare genetic calcifying arterial disease (generalized arterial calcification in infancy, GACI) causes the same calcium buildup and blockages as chronic kidney disease. Dr. Ferreira hypothesizes that life-saving drugs developed for use in GACI could help patients with long-term kidney disease by averting organ damage and eventual failure caused by the buildup of calcium crystals.
The more we learn about these rare diseases, the more we come to appreciate the tremendous implications our findings have for patients with the rare disorders and potentially hundreds of thousands of others.
About the Author
Research interests: The interactions between common genetic variations and the environment.
Common, lifelong health conditions like diabetes and hypertension have footprints that can be traced back to the womb. With advanced fetal MRI we seek to understand as much as possible about brain development during the time in utero. Non-invasive imaging technology helps us to identify signs of abnormal fetal development that may facilitate earlier diagnoses of chronic conditions and intervention.
We’re exploiting both the power and safety of MRI to develop ways to pick up early signs and signals in fetuses whose brain development may be veering off in the wrong direction. Using this advanced technology we can begin to detect varying signals or other signs of distress. These signs of distress may appear in the form of a brain chemical imbalance or a structural brain abnormality that is too subtle to be seen by an ultrasound or other scan. We now have the ability to leverage magnetic resonance imaging to examine the brain in utero for even the most subtle derailments that can lead to lifelong consequences.
The first nine months of life, when a fetus is in the womb, is a time of unparalleled growth and a critical time for fetal brain development. As we examine the maturation of the fetal brain, we know that each and every cortical fold represents future function lost or gained and lays the fundamental background or platform from which critical functions will emerge such as language and social and behavioral development.
We are developing technology that can quickly and reliably pick up early signals of a fetal brain that’s going off route to provide the ability to access therapeutic windows that are currently inaccessible. Earlier identification and intervention can improve the quality of life for children and potentially could even reverse the abnormality.
Early identification of fetal distress is critical. To be able to provide an intervention you must first be able to know that a fetus is getting into trouble, and you must be able to identify the problem early enough, in order to intervene before it has already caused injury to the fetus.
About the Author
Catherine Limperopoulos, Ph.D.
Director, MRI Research of the Developing Brain; Director, Diagnostic Imaging and Radiology/Fetal and Transitional Medicine
Research interests: Fetal neonatal brain injury
One of the first patients I ever saw with generalized arterial calcification of infancy (GACI) was actually the third child with this condition born to the same parents. GACI is a rare genetic disease, occurring in 1 of 200,000 live births. Unfortunately, as is common in GACI, two of the family’s children previously succumbed to the disorder within the first 6 weeks of life.
GACI causes calcium to build up in the arteries, causing critical blockages that reduce blood flow to organs leading to diminished function, including stroke, heart attack, and death.
Etidronate, a pyrophosphate analog developed to treat osteoporosis, has shown limited success at replacing the pyrophosphate for patients with GACI. However, more than 55 percent of children with GACI still die before their first birthday.
We need more effective solutions. Several treatment options are in development, including the administration of ENPP1 bound to an antibody, which has shown to provide a marked survival improvement in a mouse model of the disease.
These new solutions could translate to more effective treatment of GACI but also other conditions causing calcification in the arteries, particularly the calcium buildup associated with long-term kidney disease. A treatment that potentially reduces morbidity for the estimated 20 million plus Americans with chronic kidney disease would have tremendous health and economic benefits.
Developing more targeted therapies for GACI could allow this to be the outcome for many more patients, both children with GACI and potentially also patients affected by chronic kidney disease.
About the Author
Carlos Ferreira Lopez, M.D.
Until recently, doctors and patients had two choices for ordering genetic sequencing panels to identify underlying causes of disease—Individual Gene Testing (single genes and gene panels) or Whole Exome Sequencing.
Individual gene testing is the standard testing modality. Physicians identify a single gene to analyze for change or mutation. If results are negative, they order another individual test, requiring a repeat visit and another blood draw. The process is repeated again and again based on likely candidate genes for a specific disease or symptom. If a physician is very lucky, it takes only a few rounds of tests to find the culprit. More likely, however, the number of individual tests grows large, taking months of patients’ time and increasing healthcare costs significantly. By contrast, Whole Exome Sequencing includes sequencing and analyses of 25,000 genes. It is more expensive when compared with individual gene testing and takes three to six months to complete. When complete, the results often can be more than the doctor and patient bargained for: Potentially revealing a genetic problem that is unrelated to the patient’s current symptoms. A 3-year-old with seizures also may come up positive for BRCA1, the breast cancer gene. Knowing that doesn’t help understand what causes the seizures or how to best treat them. In this model, you receive everything you could ever want. Because there is so much information, however, the results are difficult to interpret or to inform treatment decisions.
We’ve come up with a different way: Personalized Sequencing Panels, a precision medicine initiative at Children’s National Health System. We offer physicians a menu of genetic regions from which to choose when they order a sequencing analysis. While a medical exome is still sequenced, we only analyze a subset of genes that the physician and geneticist think are the most likely targets, which reduces the cost and time for analysis compared to Whole Exome Sequencing. Targeting regions in this approach shortens our turnaround time for results to two or three weeks. If the first identified region shows nothing, we can return to data we’ve already collected for a second look.
We’ve been using the model for 18 months and have tested more than 1,000 patients this way. Eighty percent of physicians prefer to “create their own test” using our menu of options. Rather than bringing a one-size-fits-all test to the patient, we bring the patient their very own personalized test.