Bench to Bedside

August 2013

Presentation, Not Treatment, Responsible for Racial Disparity in Breast Cancer Survival


Researchers from The Children’s Hospital of Philadelphia and the University of Pennsylvania recently published a study in the Journal of the American Medical Association (JAMA) that shows differences in how breast cancer patients present at diagnosis are more responsible for racial disparities in 5-year survival than treatment disparities. Jeffrey H. Silber, MD, PhD, professor of Pediatrics, Anesthesiology and Critical Care at the University of Pennsylvania Perelman School of Medicine and professor of Health Care Management at The Wharton School, was the paper’s lead author.

A pediatrician and healthcare economist, since 1997 Dr. Silber has directed CHOP’s Center for Outcomes Research. Dr. Silber, who was recently named the first Nancy Abramson Wolfson Endowed Chair in Health Services Research, has published extensively on the use of multivariate matching in healthcare, and has applied this approach to outcomes research in both pediatric and adult medicine and surgery, disparities research, and cancer research.

“For 20 years, health care investigators … have been keenly aware of racial disparities in survival among women with breast cancer,” the study’s authors write. A number of potential reasons for these disparities have been put forth, including differences in screening, comorbid conditions on presentation, stage, treatment, and socioeconomic status. With the current study, the investigators sought to determine whether racial disparity in breast cancer survival was due to the way patients were treated or to their presentation at diagnosis.

The JAMA study made use of data from Medicare and the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program, which gathers “information on incidence, prevalence and survival from specific geographic areas representing 28 percent of the US population,” according to the SEER website. The researchers compared a cohort of 7,375 black women 65 years and older with three sets of 7,375 matched white control patients — matched on demographics, then demographics and presentation, and finally demographics, presentation, and treatment — selected from a pool of 98,898 potential white patients who had been diagnosed between 1991 and 2005. All of the patients studied received follow-up through December 31, 2009.

Differences in Presentation Between Whites, Blacks Found

Drs. Silber’s team found a difference in 5-year survival, with blacks displaying an absolute survival rate of just 55.9 percent, versus 66.8 percent for whites matched on demographics, an absolute disparity of 12.9 percent. When matched for presentation characteristics, the absolute difference in 5-year survival was 4.4 percent, and 3.6 percent when matched for treatment. Moreover, the difference in survival did not change significantly between 1991 and 2005.

Intriguingly, the researchers also noted a number of differences between how black and white patients presented at diagnosis. Blacks displayed higher rates of comorbidities than whites.  For example, 9.6 percent of the black patients had congestive heart failure at diagnosis, versus 5.9 percent of the demographics-matched whites. Likewise, 26 percent of blacks had diabetes versus 15.3 percent of demographics-matched whites at diagnosis.

Differences in cancer stage and size were also seen. For example, 20 percent of blacks had stage III or IV cancer at presentation, while 12 percent of demographics-matched whites were stage III or IV. And only 11.7 percent of whites matched for demographics had tumors with a diameter of 4 or more centimeters, compared to 21.6 percent of blacks.

While the study’s authors acknowledged some of its limitations — such as the inability to perform chart review to confirm diagnosis and treatment factors — the study’s results “suggest that it may be difficult to eliminate the racial disparity in survival from diagnosis unless differences in presentation can be reduced.” And though there was a “disparity in treatment,” that disparity only explains a small portion of the difference in survival between whites and blacks, with treatment differences accounting for only 0.81 percent of the 12.9 percent difference in 5-year survival, the authors note.

Overall, “treatment differences explained only a small portion of the survival difference because white women who presented like black women (i.e., were matched on demographics and presentation) but who received treatment similar to that received by white women fared almost the same as white women who presented like black women and who were treated in the same way as black women,” the study’s authors conclude.

An editorial that accompanied the publication noted that what “is notable about this study, compared with most prior research, is the use of rigorous matching methods to eliminate some of the biases that affect observational analyses.” Jeanne S. Mandelblatt, MD, MPH, of Georgetown University’s Lombardi Comprehensive Cancer Center, acted as the editorial’s corresponding author, while Vanessa B. Shephard, PhD, and Alfred I. Neugut, MD, PhD, of Georgetown and Columbia University, respectively, also contributed to the editorial.

“This rigorous study … provides additional clues to the black-white differences in breast cancer outcomes. Ultimately, for any cancer control strategy to succeed, improved care quality appears to be a necessary, but not sufficient, condition to eliminate race-based mortality differences in the United States,” said the editorial’s authors.

To read more, see the JAMA study.

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CHOP Researchers Advance New Anti-Tumor Immunotherapy Approach


By carefully adjusting the function of crucial immune cells, Children’s Hospital investigators may have developed a completely new type of cancer immunotherapy, which involves harnessing the body’s immune system to attack tumors. To accomplish this, they had to thread a needle in immune function, shrinking tumors without triggering unwanted autoimmune responses.

The new research, performed in animals, is not ready for clinical use in humans. However, the approach, which makes use of a key protein to control immune function, lends itself to further study using candidate drugs that employ the same mechanisms.

“This preclinical study demonstrates proof of principle that using a drug to regulate the function of a special, immunosuppressive subset of so-called T-regulatory (Treg) cells safely controls tumor growth,” said the study’s leader Wayne W. Hancock, MD, PhD, chief of the Division of Transplant Immunology. “It really moves the field along towards a potentially major, new cancer immunotherapy.”

Dr. Hancock and his colleagues published the study recently in Nature Medicine.

“There’s a basic paradox in immunology: why doesn’t the immune system prevent cancer in the first place?” said Dr. Hancock. The answer is complicated, he adds, but much of it involves a delicate balancing act among elements of the immune system: while immunity protects us against disease, an overly aggressive immune response may trigger dangerous, even life-threatening, autoimmune reactions in which the body attacks itself.

In the current study, Dr. Hancock focused on a subtype of immune cells called Foxp3+ T regulatory cells, or Tregs. Tregs were already known to limit autoimmunity, but often at the cost of curtailing immune responses against tumors. “We needed to find a way to reduce Treg function in a way that permits antitumor activity without allowing autoimmune reactions,” Dr. Hancock said.

The investigators showed that inhibiting the enzyme p300 can affect the functions of another protein, Foxp3, which plays a key role in controlling the biology of Tregs. By deleting the gene that expresses p300, the researchers safely reduced Treg function and limited tumor growth in mice. Notably, they also achieved the same effects on p300 and Tregs in mice by using a drug that inhibits p300 in normal mice.

Dr. Hancock plans to pursue further investigations into targeting p300 in immunotherapy. The preclinical findings offer encouraging potential for being translated into the clinic, said Dr. Hancock, who added that pharmaceutical companies have expressed interest in researching this approach as a possible cancer therapy.

The antitumor study, down-regulating Treg function, is the flip side of another part of Dr. Hancock’s Treg research. In a 2007 animal study, also in Nature Medicine, he increased Treg function with the goal of suppressing the immune response to allow the body to better tolerate organ transplants. In the current study, decreasing Treg activity permitted the immune system to attack an unwelcome visitor — a tumor. In both cases, he relied on epigenetic processes — using groups of chemicals called acetyl groups to modify key proteins — but in opposite directions.

“This is the yin and yang of immune function,” Dr. Hancock noted.

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Widespread Healthcare Access Could Lead to Influx of Pediatric Patients


New research signals that emergency and outpatient healthcare providers may need to prepare for higher demand for treatment among younger patients with mild and moderate injuries.

As policies encouraging broader health insurance coverage go into effect, researchers estimate the potential for more than 730,000 additional medically attended injuries annually, or a 6.1 percent increase if all currently uninsured children and young adults (ages 0-26) become insured. The estimates are based on 2008 injury data from the National Health Interview Survey.

The study, recently published in Clinical Pediatrics, was led by Flaura K. Winston, MD, PhD, scientific director of the Center for Injury Research and Prevention (CIRP). CHOP’s Mark R. Zonfrillo, MD, MSCE, also contributed to the study.

“In order to assist planning efforts by healthcare systems and policymakers, we aimed to examine the impact on trauma systems of increases in young people with health insurance,” said Dr. Winston. “This study signals a need to prepare for potential large increases in demand for care of minor and moderate pediatric and young adult injuries in both emergency department and outpatient settings.”

According to the study, a significant portion of the increase will come from currently uninsured young adults (18-26 year olds), who will now be able to remain on their parents insurance until age 26 or find affordable care through exchanges. The researchers found that the causes and nature of medically attended injuries differed between insured and uninsured young adults.

For example, the uninsured sought medical care for more serious injuries like fractures when compared to other types of injury, while insured patients sought medical care for a wider distribution of injuries — with the most common being sprains and strains, as well as open wounds. Among children under age 18, 11 percent of medically attended injuries among insured kids were related to overexertion, but this injury mechanism did not cause uninsured children to seek care.

Dr. Winston and her colleagues based their estimates on recent injury care data and the assumption that those new to insurance would have a probability of medically attended injury that equals that of those who already have insurance. They predict that each year as many as 510,553 additional children and young adults could be seen for injury treatment in outpatient settings.

Of those, an estimated 195,838 will visit emergency departments or will be admitted to the hospital, while another 30,689 will be attended through phone-only encounters. Dr. Winston cautions that the actual health system utilization rates and sites of care may vary as newly insured people may access care differently from those who are already insured.

“Health care delivery systems across the US need to have sufficient numbers of general and pediatric healthcare providers who are trained in treating moderate trauma and injury and can staff urgent care centers, health centers, primary care practices, call centers, and emergency departments,” said Dr. Winston. “In keeping with the aims of the Affordable Care Act, the goal should be that all young patients who seek care for their injuries get the appropriate care at the right time and right place.”

The investigators recommend several steps health care systems can take to manage the potential increase in patients and avoid both the expensive overuse of emergency services and the long-term effects on communities of inadequately treated injury:

“Injury is the leading health risk for children and young adults. Proven prevention strategies and appropriate acute care will reduce fatalities and the long-term consequences that injury can have on quality of life,” said Dr. Winston.

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Current Techniques to Prevent Lung Injury in Babies Less Effective than Expected


A Children’s Hospital neonatologist is the senior author of a new study showing current non-invasive techniques for respiratory support are less effective than assumed in reducing the incidence of severe lung injury in very premature infants. Neonatologists commonly use non-invasive nasal ventilation instead of mechanical ventilation via a breathing tube, in hopes of avoiding bronchopulmonary dysplasia (BPD).

Frequently a by-product of intubation, BPD­ — scarring and inflammation of the lungs — is a leading cause of death or neurological injury in extremely-low-birth-weight infants.

This multinational, randomized trial, which was led by Children’s Hospital’s Haresh Kirpalani, MD, compared two common forms of non-invasive ventilation used in extremely-low-birth-weight premature infants. Both techniques make breathing easier for the infant by stopping the lungs from collapsing, which over time causes lung inflammation and injury.

The current standard of care, nasal continuous positive airway pressure (CPAP), delivers slightly pressurized air throughout the breathing cycle. In contrast, nasal intermittent positive-pressure ventilation (IPPV), which has become widespread, provides an additional spike of positive pressure when the infant inhales. While more complicated, the hope had been that IPPV was more effective than standard CPAP.

With this study, the researchers tested the hypothesis that the extra pressure delivered via IPPV would be more beneficial than CPAP in preventing BPD. The study team randomly assigned 1009 infants with a birth weight under 1000 grams (2.2 pounds) and gestational age under 30 weeks to either nasal CPAP or nasal IPPV. The infants were from 34 neonatal intensive care units in 10 countries.

Dr. Kirpalani and his team found no significant difference in the primary outcome of either death or survival with BPD at 36 weeks. They also found no significant difference in rates of other neonatal complications between the two treatment groups.

“Although somewhat discouraging, this research is significant as it refutes the common assumption that the non-invasive therapies being used are reducing severe lung injury in these tiny babies,” said Dr. Kirpalani. “The study alerts us that we still need to develop new therapies for babies to avoid lung injury and BPD.”

The study was published recently in the New England Journal of Medicine.  To learn more about CHOP’s newborn care and research, see theDivision of Neonatology.

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St. Baldrick’s Foundation Awards Children’s Hospital More than $650,000


The St. Baldrick’s Foundation recently announced $699,186 in grants to one consortium and three cancer researchers at Children’s Hospital. The foundation made awards to the Testicular Cryopreservation Consortium and to investigators Shannon Maude, MD, PhD, Michael Hogarty, MD, and Vandana Batra, MD.

Known for its head-shaving events — where volunteers have their heads shaved in solidarity with children fighting cancer — the St. Baldrick’s Foundation has distributed more than $100 million in research grants to support childhood cancer research since 2005. The recently announced grants to CHOP are among 63 grants totaling $22 million to be announced during the summer of 2013.

The award to the Testicular Cryopreservation Consortium — which is led by Children’s Hospital — will support efforts to allow boys being treated for cancer to freeze testicular tissue to preserve their fertility for the future.

“We are so grateful that St. Baldrick’s has awarded us another year of funding,” said Jill Ginsberg, MD, director of the Hospital’s Cancer Survivorship Program. “We are hopeful that advances in the laboratory will make it possible for these boys to achieve fertility when they are ready to start a family. This work could not have been accomplished without the support of St. Baldrick’s Foundation.”

The award to Dr. Maude, a St. Baldrick’s Scholar award given over three years, will support her work on acute lymphoblastic leukemia (ALL). The most common form of childhood leukemia, ALL is largely curable, with an 85 percent cure rate. However, the other 15 percent of ALL patients face limited treatment options, so researchers have been looking for novel ways to treat this disease.

“The St. Baldrick’s Scholar award provides pivotal support in a young investigator’s career,” said Dr. Maude, who added that she was “very grateful to the St. Baldrick’s Foundation for enabling me to pursue a research career with the goal of finding new treatments for difficult to treat forms of ALL.”

Dr. Michael Hogarty was awarded an $110,000 St. Baldrick’s Research Grant to support his neuroblastoma research. Affecting the peripheral nervous system, neuroblastoma usually appears as a solid tumor in a child’s chest or abdomen. Though only comprising 7 percent of all childhood cancers, it causes 10 to 15 percent of all childhood cancer-related deaths. Neuroblastoma is also notoriously complex, with a broad number of gene changes that can give rise to the disease.

Dr. Hogarty — who also recently received an award from Alex’s Lemonade Stand Foundation — has been studying the epigenetics of neuroblastoma, supported in part with earlier funding from St. Baldrick’s Foundation.

And last but certainly not least, Dr. Batra, an attending physician in CHOP’s Cancer Center, was awarded $134,186 to fund an additional year of her neuroblastoma investigation. Dr. Batra has been leading a study of the drug 211At-MABG, to treat neuroblastoma more effectively and with fewer side effects.

“Successful completion of this project funded by St Baldrick’s will help fill the void of novel therapeutic approaches and will ultimately lead to the incorporation of a new targeted radiotherapeutic 211At-MABG into frontline approaches to high-risk neuroblastoma therapy,” said Dr. Batra.

To learn more about the awards, see the press release from St. Baldrick’s Foundation.

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Training Program Seeks to Confront Neurodevelopmental Disabilities


Roughly 10 percent of American households live with an individual with a neurodevelopmental disability, every day grappling with the emotional, logistical, and financial burdens brought on by these conditions.

Specifically, 2010 data from the U.S. Census shows that approximately 1.2 million American adults, or 0.5 percent of the population, had an intellectual disability or mental retardation, while 0.4 percent of Americans over the age of 18 — 944,000 people — had some measure of cognitive disability. And according to recent data published by the American Community Survey, 3.8 percent of children in metropolitan areas and 4.8 percent outside metropolitan areas have a “cognitive difficulty.”

The Hospital’s Neurodevelopmental Disabilities Training Program (NDTP) was established as a joint initiative of The Children’s Hospital of Philadelphia and the University of Pennsylvania in 1998 and is supported by the National Institutes of Neurologic Disorders and Stroke (NINDS).  Children’s Hospital neuroscientist Michael Robinson, PhD, was one of the co-founders and currently serves as the director of the program, which recently received another five years of funding totaling more than $1.7 million from NINDS.

“These disorders have diverse genetic and environmental causes, but they share many co-morbidities. For example, seizures or anxiety disorders are frequent symptoms of Fragile X and other autism spectrum disorders. Therefore the rationale was to bring together researchers from diverse training backgrounds and scientific expertise to both advance interdisciplinary training and encourage collaboration,” said Dr. Robinson.

Support for the program also comes from the L. Morton Morley Funds of the Philadelphia Foundation and The Children’s Hospital Research Institute. These additional sources help support the program’s administration and provide supplements to encourage clinicians to engage in full-time research training after they have completed their clinical training.

“Even at this time of tight fiscal constraint by the federal government, the societal, human, and economic costs of intellectual disability provide ample justification for continued training. It is these trainees who provide hope for the future,” Dr. Robinson added.

An Emphasis on Mentorship

 The NDTP pairs trainees with faculty mentors, who provide advanced research training designed to help the trainees achieve their career goals. CHOP faculty members who have served as mentors in the past include Douglas Wallace, PhD director of the Center for Mitochondrial and Epigenomic Medicine; Douglas Coulter, PhD director of CHOP’s Epilepsy Research Lab; and Robert Schultz, PhD director of the Center for Autism Research. In all, 31 different mentors have supervised trainees.

In addition to working closely with a mentor, NDTP trainees attend lectures and seminars, take courses, participate in clinical practica, and develop other skills, such as grant writing. The NDTP has three broad areas of focus: chromosomal/genetic causes of neurodevelopmental disabilities, acquired/environmental causes, and neurobehavioral disorders, Dr. Robinson said.

Trainees who have taken part in the program come from a variety of disciplines, including neurology and neuroscience, physics, and clinical psychology. To date, the NDTP has enrolled 36 trainees, which includes a mix of MDs, PhDs, and MD/PhDs. Of the 26 trainees who have completed training, 13 have taken faculty positions at prestigious academic institutions across the country and continue their studies.

For example, Carrie Bearden, PhD, who was supported by the program from 2001 to 2002, is now an associate professor of Psychology at the University of California, Los Angeles, and is recognized internationally for her work studying contributions of genetic and environmental factors to mood disorders in adolescents. More recently, Adam Woods, PhD who was supported from 2010 until June of 2013, landed a faculty position at the University of Florida. All of the graduates continue to further research or treatment in a variety of positions, including at pharmaceutical firms.

“It is gratifying to support such a talented group of individuals. Like a parent, I’m proud of the accomplishments of these trainees.” Dr. Robinson noted.

The program supports six trainees at any one time, current trainees include: Nayla Chaijale, PhD; Jessica Panzer, MD, PhD; Lucia Peixoto, PhD; Jill See, PhD; and Chia-Yen Wu, PhD.  Dr. Chaijale, who received her PhD from Drexel University in 2010, is studying how chronic stress changes brain development with Rita Valentino, PhD. Dr. Panzer, who received her MD/PhD degrees from the University of Pennsylvania, has been studying contributions of the immune system to neurobehavioral disorders with David Lynch, MD, PhD.

Dr. Peixoto, who received her PhD from the University of Pennsylvania, has been learning how the environment modifies genetic profiles during learning while working with Ted Abel, PhD.  Dr. See, who also received her PhD from the University of Pennsylvania, has been working with Akiva Cohen, PhD, to examine the efficacy of a new therapy to limit the damage associated with traumatic brain injury. And last but not least, Dr. Wu, who received her PhD from the University of Delaware in 2011, is working with Robert Kalb, MD to test possible approaches to limiting motor neuron loss observed in spinal muscular atrophy.

“We try to emphasize strong mentoring, and focus on supporting the trainees as they move forward in their careers,” Dr. Robinson said.

The Neurodevelopmental Disabilities Training Program is one of many educational programs offered by Children’s Hospital, and one of several geared toward research. Other training programs’ areas of focus include cardiology, diabetes research, epidemiology and outcomes research, pediatric hematology, and genetics. To learn more, see the CHOP Research Education page.

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Reprogramming Stem Cells Offers Powerful Tool for Studying, Treating Diseases


First produced in the past decade, human induced pluripotent stem cells are capable of developing into many or even all human cell types. In new research, scientists reprogrammed skin cells from patients with rare blood disorders into induced pluripotent stem cells (iPSCs), highlighting the great promise of these cells in advancing understanding of those challenging diseases — and eventually in treating them.

“The technology for generating these cells has been moving very quickly,” said the studies’ leader, Mitchell J. Weiss, MD, PhD. “These investigations can allow us to better understand at a molecular level how blood cells go wrong in individual patients — and to test and generate innovative treatments for the patients’ diseases.”

Dr. Weiss, a hematologist and stem cell researcher, along with CHOP’s Monica Bessler, MD, Philip Mason, PhD, and Deborah L. French, PhD, published a study on iPSCs and Diamond Blackfan anemia, a rare congenital blood disorder. Another study published by Dr. Weiss and his team in the same journal on April 25 focused on iPSCs in the childhood cancer juvenile myelomonocytic leukemia.

In Diamond Blackfan anemia (DBA), a mutation prevents a patient’s bone marrow from producing normal quantities of red blood cells, resulting in severe, sometimes life-threatening anemia, which can make it difficult for researchers to discern the underlying mechanism of the disease. According to the Diamond Blackfan Anemia Foundation, there are 25 to 35 new cases of the disease a year in the U.S., with more than 90 percent of patients showing symptoms in the first year of life.

“It’s very difficult to figure out what’s wrong, because the bone marrow is nearly empty of these cells,” said Dr. Bessler, the director of CHOP’s Pediatric and Adult Comprehensive Bone Marrow Failure Center.

Programming Patients’ Cells

 In the June Blood study, the researchers removed fibroblasts (skin cells) from DBA patients and using proteins called transcription factors reprogrammed the cells into iPSCs. As those iPSCs were stimulated to form blood tissues, like the patient’s original mutated cells, they were deficient in producing red blood cells. However, when the researchers corrected the genetic defect that causes DBA, the iPSCs developed into red blood cells in normal quantities.

“This showed that in principle, it’s possible to repair a patient’s defective cells,” said Dr. Weiss, who cautioned that this finding is an early step, with further studies needed to verify if this approach will be safe and effective in clinical use.

However, he added, the patient-derived iPSCs are highly useful as a model cell system for investigating blood disorders. For instance, DBA is often puzzling, because two family members may have the same mutation, but only one may be affected by the disease. Because each set of iPSCs is specific to the individual from whom they are derived, researchers can compare the sets to identify molecular differences, such as a modifier gene active in one person but not the other.

Furthermore, the cells offer a renewable, long-lasting model system for testing drug candidates or gene modifications that may offer new treatments, personalized to individual patients, Dr. Weiss noted.

The study of juvenile myelomonocytic leukmia published in April, meanwhile, provides a concrete example of using iPSCs for drug testing, specifically for the rare and often-aggressive childhood leukemia JMML. First the study team generated iPSCs from two children with JMML, and then manipulated the iPSCs in cell cultures to produce myeloid cells that multiplied uncontrollably, much as the original JMML cells do.

They then tested the cells with two drugs, each of which able to inhibit a separate protein known to be highly active in JMML. One drug, an inhibitor of the MEK kinase, reduced the proliferation of cancerous cells in culture. “This provides a rationale for a potential targeted therapy for this specific subtype of JMML,” said Dr. Weiss.

Children’s Hospital’s human embryonic stem cell/induced pluripotent Stem Cell (hESC/iPSC) Core facility — which is directed by the studies’ co-author Dr. French — generated the iPSCs lines used in these studies. The facility’s goal is to develop and maintain standardized iPSCs lines specific to a variety of rare inherited diseases like DBA and JMML, including dyskeratosis congenita, congenital dyserythropoietic anemia, thrombocytopenia absent radii (TAR), Glanzmann’s thrombasthenia and Hermansky-Pudlak syndrome.

A long-term goal of this line of research, said Dr. Weiss, is for the iPSC lines to provide the raw materials for eventual cell therapies that could be applied to specific genetic disorders. “The more we learn about the molecular details of how these diseases develop, the closer we get to designing precisely targeted tools to benefit patients.”

The study was published in June in the journal Blood.

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Children’s Hospital Investigators Discover Mitochondrial Signaling Response


Mitochondria are tiny biological structures that act as our cell’s power plants, extracting energy from nutrients to drive the body. When mitochondria malfunction, they may impair the function of potentially any organ in the body, in a bewildering variety of ways. Mitochondrial disease can have widely varying effects and severity, ranging from blindness to exercise intolerance to death, often wreaking progressive havoc over time in both children and adults.

Researchers from Children’s Hospital have identified a master network of signaling molecules that acts like a “fuse box” to regulate the cellular effects of defective energy flow in mitochondrial respiratory chain diseases — a diverse set of difficult-to-treat genetic-based energy disorders. Using that knowledge, they showed that a form of vitamin B3 called nicotinic acid partially restores normal functioning in cells taken from patients with mitochondrial disease.

The study, which was led by Marni J. Falk, MD, director and attending physician in the Mitochondrial-Genetic Disease Clinic, suggests that the regulatory signaling network may offer a common avenue to target in developing effective, personalized treatments for many mitochondrial energy disorders.

“Finding a common cellular response reveals that some order exists in the chaos of these basic energy diseases,” said Dr. Falk. “Identifying the central factors regulating manifestations of mitochondrial disease is like troubleshooting a household electrical system: instead of analyzing problems that may occur at each individual light bulb or switch plate, we have located a central problem in the fuse box.”

Primary mitochondrial diseases directly interfere with the function of the respiratory chain (RC) — the highly conserved sequence of chemical reactions within mitochondria that generate energy from oxygen and nutrients.

“There are hundreds of different individual reasons for RC malfunction,” said Dr. Falk, “but we identified a common cellular response — an integrated, nutrient-sensing signaling network — that recognizes when energy flow is impaired. That response alters a host of biological pathways, and in many tissues, those secondary biochemical changes are actually contributing to the symptoms of disease.”

RC malfunction in mitochondrial disease may cause symptoms such as seizures, strokes, blindness, heart disease, progressive muscle weakness, and vulnerability to infections. No cure exists, and most current treatments for RC diseases are largely ineffective.

In the current study, Dr. Falk and her team analyzed cellular responses in human skeletal muscle and skin cell lines, finding that RC disease disrupted crucial biological pathways controlled by a handful of master signaling factors, including FOXO, PPAR, sirtuins, AMPK, and mTORC1. All of those factors are integral components of cellular signaling networks that sense nutrient availability and regulate growth.

“The good news in our research is that the signaling pathways regulating the body’s response to mitochondrial disease are already well-known for other reasons,” said Dr. Falk. “Using an agent that restores their collective activity toward more normal functioning offers potential treatments for the diverse symptoms of mitochondrial RC disease.”

Building on her team’s previous animal studies, which showed that a cholesterol-lowering drug called probucol restored kidney function in a mouse model of an RC defect, Dr. Falk and colleagues used a form of vitamin B3, nicotinic acid, in their current study. Like probucol, nicotinic acid is known to stimulate the PPAR signaling pathway. Here, they added nicotinic acid to a cell line grown from the skin of a patient with the mitochondrial disease known as Leigh syndrome that causes strokes in young children.

The results were exciting. The nicotinic acid normalized signaling activity not just in PPAR, but across an integrated signaling network, and also improved overall cellular respiration — the cells’ ability to use oxygen. “Even though the underlying genetic defect in RC function persisted, we were able to reverse some of its major deleterious downstream effects on crucial cellular functions that are impaired in many varieties of mitochondrial disease,” Dr. Falk noted.

More work remains to be done to determine if this discovery in patient tissues and cell culture may lead to effective clinical treatments. Nonetheless, “finding a central signaling mechanism common to highly diverse RC disease should allow researchers to better classify subtle differences in this signaling response to understand subtypes mitochondrial disease and fashion personalized treatments that restore specific signaling alterations identified in individual patients,” Dr. Falk said.

Dr. Falk and her colleagues published their study in the journal PLOS ONE.

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Share Your Story!


The success stories from CHOP Research are incredible. They have the power to connect investigators who can combine unique approaches for enhanced success, inspire donors to contribute the resources necessary to take a project to its next step, and provide hope for families struggling with childhood disease. Sharing your story is essential so that we can spread the word about the amazing, groundbreaking work accomplished every day at CHOP Research.

We want to know your story, your news, your success. Many steps in the research process are newsworthy. Some of the things we are interested in include:

The Research Institute benefits from a spirit of collaboration that extends beyond the workbench. We encourage you to share not only your news, but also the news of your CHOP Research colleagues.

Please share your news with us by contacting Jennifer Long, director of Research Communications.

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