The finding:

Children’s Hospital of Philadelphia investigators revealed the biological events by which some cancer cells develop resistance to a groundbreaking cellular therapy, called CAR T-cell therapy, that has successfully treated many patients with particular forms of leukemia. They also found clues to a possible method to overcome the cancer’s resistance.

Why it matters:

Chimeric antigen receptor (CAR) T-cell therapy, also called CAR T-cell therapy, represents a landmark achievement in personalized cancer immunotherapy — harnessing the body’s immune cells to treat cancer. The therapy has dramatically improved survival in children and young adults who relapsed or never responded to their initial chemotherapy. However, some 20 to 30 percent of patients with acute lymphoblastic leukemia (ALL) receiving CAR T-cell treatment either never respond or develop resistance within a few weeks.

Who conducted the study:

Andrei Thomas-Tikhonenko, PhD, chief of the Division of Cancer Pathobiology and a professor with the Departments of Pathology and Laboratory Medicine and Pediatrics at CHOP, led the study.

How they did it:

The researchers built upon their previous study showing that mutations in the leukemia cell hamper a protein, called CD19 antigen, that is essential for CAR T-cell therapy to succeed. The CD19 antigen needs to be produced in sufficient quantities to be recognized by CAR T cells. Some of the originally discovered mutations prevent CD19 from ever being produced. Yet other seemingly innocuous mutations would simply insert a few extra elements into the protein’s amino acid chain. How such insertional mutations could cause resistance to therapy was not clear.

The recent study focused on the biological mechanisms at work.

For CD19 to be recognized by CAR T cells, it first needs to reach the surface of the leukemia cell. The researchers found that the insertional mutations cause the CD 19 antigen to misfold within the cell so that it can’t be carried to the cell surface intact, and is instead retained in the structure called the endoplasmic reticulum. However, they also found that misfolded CD19 proteins are tightly bound to the machinery that breaks down full-length proteins into short peptides and transports them to the cell surface for immune recognition.

Quick thoughts:

“Experimental science is capricious and utterly unpredictable,” said Dr. Thomas-Tikhonenko, regarding the study. “It doesn’t care about gaps in your education, and more often than not takes you in directions you would rather avoid. Before we embarked on this project, my knowledge of protein folding and intracellular transport had been limited to undergraduate-level cell biology textbooks written one millennium ago. Talk about on the job training!”

What’s next:

The team’s next steps are to investigate whether mutant CD19 peptides indeed reach the leukemia cell’s surface, and then to generate T cells that recognize and attack that peptide.

Where the study was published:

The study appeared in the journal Molecular and Cellular Biology.

Who helped fund the study:

A variety of public and private sponsors. National Institutes of Health, William Lawrence and Blanche Hughes Foundation, Alex's Lemonade Stand Foundation, and St. Baldrick’s-Stand Up To Cancer Pediatric Cancer Dream Team.

Where to learn more:

Learn more about this study in this CHOP press release.

The finding:

Using data analysis tools and three-dimensional studies of genomic geography, researchers found new risk genes for osteoporosis, opening the door to potentially more effective treatments.

Why it matters:

The research team identified two novel genes that affect bone-forming cells relevant to fractures and osteoporosis. As a potential added benefit, the analytical methods the researchers used could be applied more broadly to other diseases with a genetic component, including certain pediatric cancers, diabetes, and lupus.

Who conducted the study:

Struan F.A. Grant, PhD, and Andrew D. Wells, PhD, directors of the Center for Spatial and Functional Genomics (CSFG) at Children’s Hospital of Philadelphia, co-led the study.

How they did it:

Dr. Grant and his colleagues investigated genetic loci, or DNA regions, previously established to be associated with bone mineral density in genome-wide association studies (GWAS), both in adults and children. They used state-of-the-art massively parallel, high-resolution tools to analyze genome-wide interactions in human osteoblasts — bone-forming cells derived from mesenchymal stem cells. Their analytical tools used a “multi-omic” approach, integrating data from the genome sequence and details of chromatin structure to map interactions between potential bone mineral density (BMD)-related gene promoters and regions harboring genetic variants related to BMD biology. The study pinpointed two novel genes, ING3 and EPDR1, which in turn revealed strong effects on human osteoblasts.

Quick thoughts:

“The geography of the genome is not linear,” Dr. Grant said. “Because DNA is folded into chromosomes, parts of the genome may come into physical contact, enabling key biological interactions that affect how a gene is expressed. That’s why we study the three-dimensional structure of the genome.”

What’s next:

Follow-up studies investigating the biological pathways affected by one of the genes, ING3, identified in the study may present targets for therapies to strengthen bone mineral density and ultimately prevent fractures.

Where the study was published:

The study appeared in the journal Nature Communications.

Who helped fund the study:

The National Institutes of Health supported this research study.

Where to learn more:

Learn more about the study in this CHOP press release.

The finding:

A large international research team discovered a new genetic cause for a severe, difficult-to-treat childhood form of epilepsy, identifying spontaneous mutations in a brain-expressed calcium channel that result in epileptic overactivity. The team’s research in patients also found clues to potential medical treatments for the rare condition.

Why it matters:

The study focused on disease-causing changes in the CACNA1E gene. This gene was long suspected to play a key role in regulating electrical activity in brain cells, but it was not yet known as a cause for a human disorder. Their study was the first to link this gene to human epilepsy and to demonstrate that overactivity of the ion channel encoded by CACNA1E leads to severe early-onset epilepsy.

Who conducted the study:

Katherine L. Helbig, MS, CGC, co-director of the Epilepsy NeuroGenetics Initiative (ENGIN) and senior genetic counselor in the Division of Neurology at Children’s Hospital of Philadelphia, served as first author on the study. The full research team included nearly 100 scientists, from Europe, Canada, China, Australia, New Zealand, and the United States.

How they did it:

The study team performed next-generation sequencing, including whole exome sequencing, in 30 infants and young children with severe epilepsy, and identified disease-causing variants in CACNA1E. In most cases, the gene variants were de novo — present in the affected children, but not found in their parents. De novo variants are being increasingly found in severe childhood epilepsies.

Quick thoughts:

“The fact that we were able to identify 30 patients at this stage of research indicates that we could be looking at a more common cause of genetic epilepsy than we would have initially assumed,” Helbig said. “This research enables us to give some families an answer as to why their child has severe epilepsy. It also offers the potential that we can build on this knowledge to find new strategies for treatment.”

What’s next:

Most of the 30 patients did not respond to any anti-epileptic medications, except for a few who responded to the medication topiramate, known to target the CACNA1E channel. Further studies will focus on this finding and other aspects of the team’s research, with the aim of translating their knowledge into targeted precision therapies for children with severe genetic epilepsy.

Where the study was published:

The study appeared in the American Journal of Human Genetics. 

Who helped fund the study:

The study was supported by multiple sources worldwide, including national medical institutes of various countries, the U.S. National Institutes of Health (grant NS069605), and the Deciphering Developmental Disorders study, sponsored by the Wellcome Trust.

Where to learn more:

Learn more about this study in this Cornerstone blog story or this CHOP press release.

The finding:

Researchers at Children’s Hospital of Philadelphia examined differences in the way girls and boys on the autism spectrum use certain types of words during storytelling. The investigators found that autistic girls used significantly more “cognitive process” words such as “think” and “know” than autistic boys, despite comparable autism symptom severity. Identifying differences like these can open the door to ensuring that girls with autism spectrum disorder (ASD) receive the diagnosis and support they need to achieve the best possible quality of life.

Why it matters:

Boys are four times more likely than girls to be diagnosed with ASD, yet a growing body of research shows that the condition is more common in girls than previously thought, strongly suggesting that new methods are required to diagnose the disorder at younger ages.

Who conducted the study:

Julia Parish-Morris, PhD, a scientist in the Center for Autism Research and faculty member in the Departments of Child Psychiatry and Biomedical & Health Informatics at CHOP, led the study.

How they did it:

Dr. Parish-Morris and her co-authors studied 102 verbally fluent school-aged children who either had a diagnosis of ASD (21 girls and 41 boys) or were typically developing (19 girls and 21 boys), and were matched on age, IQ, and maternal education. Children viewed a sequence of pictures involving a fisherman, a cat, and a bird, and then told a story based on what they saw.

Results revealed that autistic girls used significantly more cognitive process words than autistic boys did, even when they had similar levels of autism severity. Girls with ASD and typical girls used comparable numbers of cognitive process words. Autistic boys and girls both used more nouns than typically developing children, demonstrating object-focused storytelling. Autistic girls therefore showed a unique narrative profile that overlapped with typical children as well as with autistic boys.

Quick thoughts:

“In order to place these findings in context, it’s important to understand that because girls tend to exhibit different traits than autistic boys do, they are often incorrectly diagnosed or missed entirely by standard diagnostic tools. That discrepancy also skews the research literature,” Dr. Parish-Morris said. “Autism studies have historically included three to six times as many males as females. This means that we don’t yet know enough about gender differences in autism, and so we miss girls whose traits differ from those of boys.”

What’s next:

Sex-informed screening and diagnostic methods may help physicians identify autism in verbal girls at an earlier age, which should spur efforts to develop appropriate, personalized early interventions resulting in improved support for girls and women with ASD.

Where the study was published:

The study appeared online in the journal Molecular Autism.

Who helped fund the study:

The Autism Science Foundation, the Eagles Charitable Trust, the McMorris Family Foundation, the Allerton Foundation, and a National Institutes of Child Health and Human Development supported the study.

Where to learn more:

Learn more about this research by reading this CHOP press release.

The finding:

Teen drivers diagnosed with attention-deficit/hyperactivity disorder (ADHD) are significantly more likely to crash, be issued traffic and moving violations, and engage in risky driving behaviors than their peers without ADHD.

Why it matters:

By highlighting the specific types of crashes and traffic violations, the study identified risky driving behaviors that those with ADHD may be more likely to engage in — such as driving while intoxicated, not wearing a seat belt, and speeding.

Who conducted the study:

Allison E. Curry, PhD, MPH, a senior scientist and director of Epidemiology and Biostatistics at the Center for Injury Research and Prevention at Children’s Hospital of Philadelphia and an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, led the study.

How they did it:

The multidisciplinary team of researchers from CHOP’s Center for Injury Research and Prevention and Center for Management of ADHD analyzed detailed crash and traffic violation records for newly licensed drivers to conduct the first large-scale longitudinal study. They reviewed the records of 14,936 adolescents and linked the adolescents’ electronic health data with New Jersey driver licensing records, traffic violations, and police-reported crash data. Within this group, the researchers identified 1,769 adolescents with childhood-diagnosed ADHD who obtained an intermediate driver’s license during the study period, and compared their crash outcomes with those of the drivers without ADHD.

The study team found the crash rate was 62 percent higher for those with ADHD the first month after getting licensed, and 37 percent higher during the first four years after licensure, regardless of their age when licensed. They also found the rates of traffic and moving violations were significantly higher among young drivers with ADHD as compared to those without ADHD. Among these drivers, nearly 37 percent were issued a traffic violation, and nearly 27 percent a moving violation within their first year of driving, compared to 25 percent and 18 percent respectively among their peers without ADHD. Drivers with ADHD had higher rates of alcohol or drug violations and moving violations (including speeding, nonuse of seat belts, and electronic equipment use).

Quick thoughts:

“What this study suggests is that we have to go beyond current recommendations of medication and delaying the age of getting licensed to decrease crash risk for teens with ADHD,” Dr. Curry said. “Their higher rate of citations suggest that risky driving behaviors may account for why they crash more. More research is needed to objectively measure if and how these behaviors specifically contribute to crash risk.”

What’s next:

Additional research is needed to understand the specific mechanisms by which ADHD symptoms influence crash risk so that researchers can develop skills training and behavioral interventions to reduce the risk for newly licensed drivers with ADHD. Because the behaviors identified in the study are amenable to change, clinicians and families can ultimately work with this at-risk group of teens to practice safe driving behaviors and potentially reduce their crash risk.

Where the study was published:

The study appeared online in the journal Pediatrics.

Who helped fund the study:

The Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health supported the research.

The finding:

New research presents an alternative model for healthcare providers that focuses on serving the needs of vulnerable infants who are hospitalized and separated from their mothers. The resource is called the Spatz 10-Step and Breastfeeding Resources Nurse Model to Improve Human Milk and Breastfeeding Outcomes.

Why it matters:

Mothers of critically ill infants may not receive necessary breastfeeding support because their babies may be taken directly to a newborn intensive care unit or to surgery. The 10-Step Model consists of informed decision, establishment and maintenance of milk supply, human milk management, oral care and feeding of human milk, skin-to-skin care, non-nutritive sucking, transition to breast, measuring milk transfer, preparation for discharge, and appropriate follow-up.

Who conducted the study:

Diane Spatz, PhD, RN-BC, FAAN, nurse-researcher and founder of the Breastfeeding and Lactation Program at Children’s Hospital of Philadelphia developed these models.

How they did it:

Dr. Spatz drew upon her own extensive clinical experience and on her NIH funding research studies to create the Spatz 10-Step and Breastfeeding Resources Nurse Model to Improve Human Milk and Breastfeeding Outcomes.

Quick thoughts:

“Because nurses are the largest health profession globally and in the U.S., nurses should play a critical role in providing evidence-based lactation care and support,” Dr. Spatz said. “At CHOP, we developed a specialized educational and training program so that nurses across the institution could implement the 10-step model effectively.”

Where the study was published:

The study appeared in the Journal of Perinatal Neonatal Nursing.

Where to learn more:

Learn more about this study in this CHOP press release.

The finding:

Scientists using a powerful new technology that sequences RNA in 20,000 individual cell nuclei uncovered new insights into biological events in heart disease. The researchers worked with animal studies to identify a broad variety of cell types in both healthy and diseased hearts, and they investigated in rich detail the “transcriptional landscape” in which DNA transfers genetic information into RNA and proteins.

Why it matters:

While the heart is a complex organ, with a multitude of cell types, much still remains to be understood about mammalian heart development and heart disease, especially during the postnatal period. This research provided key insights into normal heart development, heart disease, and gene regulatory mechanisms of a heart hormone called GDF15. The findings lay the groundwork for a greater understanding of cardiac biology and may ultimately lead to targeted therapies aimed at key gene networks that could offer better treatments for heart patients.

Who conducted the study:

Liming Pei, PhD, a molecular biologist in the Center for Mitochondrial and Epigenomic Medicine (CMEM) at Children’s Hospital of Philadelphia and an associate professor in the Department of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania, and Hao Wu, PhD, an assistant professor of Genetics at Penn Medicine co-led the study.

How they did it:

The research team was the first to adapt massively parallel single-nucleus sequencing (snRNA-seq) technology for use in postnatal heart tissue. They used the snRNA-Seq method termed sNucDrop-seq to analyze nearly 20,000 nuclei in heart tissue from normal and diseased mice, focusing on cardiomyopathy.

The sequencing tool identified major types of heart cells, such as cardiomyocytes, fibroblasts, and endothelial cells, as well as more rare cardiac cell types. The study team found great variety among each cell type, as well as indications of functional changes in the heart cells during both normal development and diseased conditions.

Another finding concerned gene networks that regulate production of cardiac hormones in heart disease — specifically GDF15. The cardiac synthesis and secretion of GDF15 is increased in heart disease, which slows overall body growth by inhibiting liver growth hormone action and helps reduce the energetic demands on a damaged heart. Such signaling could reveal more about the biological mechanisms that underlie the growth restriction commonly seen in children with congenital heart disease.

Quick thoughts:

“This is the first time to our knowledge that massively parallel single-nucleus RNA sequencing has been applied to postnatal mouse hearts, and it provides a wealth of detail about biological events in both normal heart development and heart disease,” Dr. Pei said. “Ultimately, our goal is to use this knowledge to discover new targeted treatments for heart disease. In addition, this type of large-scale sequencing may be broadly applied in many other fields of medicine.”

What’s next:

Future work by the research team will center on investigating how heart disease progresses over a longer timespan than the early postnatal period. The research tool may also offer opportunities to investigate diseases in organs and systems beyond the heart. Indeed, Dr. Pei’s lab is working together with other investigators at CHOP and elsewhere using such single-cell genomics methods to advance our understanding of pediatric biology and disease, including the ambitious goal of a Pediatric Cell Atlas to define the growth phase of human development at single-cell resolution.

Where the study was published:

The study appeared in the journal Genes & Development.

Who helped fund the study:

The National Institutes of Health, the Department of Defense, and the W.W. Smith Charitable Trust provided funding for the study.

Where to learn more:

Learn more about this study in this CHOP press release.

The finding:

Researchers discovered a way to grow human stem cells destined to become mature sperm, in an effort to provide fertility options later in life to males who are diagnosed with cancer and undergo chemotherapy and radiation as children. 

Why it matters:

According to the American Cancer Society, about one in 530 young adults between the ages of 20 and 39 years is a survivor of childhood cancer. Cancer treatments leave many boys infertile, as chemotherapy and radiation often kill spermatogonial stem cells (SSCs). While there are ways to preserve fertility for boys diagnosed with cancer after puberty, no such options exist for prepubescent boys.

Who conducted the study:

Sandra Rveom, PhD, of the Perelman School of Medicine at the University of Pennsylvania; Jill Ginsberg, MD, a pediatric oncologist and director of the Cancer Survivorship Program at Children’s Hospital of Philadelphia; and Thomas Kolon, MD, attending pediatric urologist in the Division of Urology at CHOP, co-led the study.

How they did it:

Researchers have known that the production of sperm could be restored in mice that were sterilized after chemotherapy by injecting spermatogonial stem cells into their seminiferous tubules in the testes. From this, oncologists suggested that SSCs might be harvested from boys before the start of chemotherapy and reintroduced into their testes when treatment was complete. However, the testes of prepubescent boys contain such a small number of SSCs that, in order for this approach to be successful, the cells would need to be grown and multiplied in the lab prior to subsequent reinjection.

Given these challenges, the investigators identified testicular endothelial cells as a critical niche population for the maintenance and expansion of human SSCs in the lab. Additionally, they also identified five growth factors produced by testicular endothelial cells needed to keep human and mouse SSC cultures alive over the long term. Mouse cells in long-term culture restored the ability to produce sperm after chemotherapy-induced infertility. Researchers are hopeful that eventually patient samples containing the human SSCs could be expanded and used similarly when needed.

Quick thoughts:

“We have never had any fertility preservation options for prepubescent boys,” Dr. Ginsberg said. “The findings in this work are a great first step forward for our youngest patients.”

What’s next:

The next step in the research is to determine whether it is possible to re-inject or engraft the expanded SSCs into patients after they are cancer free.

Where the study was published:

The study appeared in the journal Nature Communications.

The finding:

A skin patch measuring just over an inch long containing trace amounts of milk protein may be useful in treating children with a painful, chronic condition called eosinophilic esophagitis (EoE) triggered by milk.

Why it matters:

This is the first study to examine how this treatment, called epicutaneous immunotherapy, may help children with milk-induced EoE, a food-based disease that is not helped by traditional allergy testing. If left untreated, EoE may lead to a narrowing of the esophagus due to scarring.

Who conducted the study:

Jonathan Spergel, MD, PhD, chief of the Allergy Program at Children’s Hospital of Philadelphia, led the study.

How they did it:

The pilot study followed 20 children ages 4 to 17 with EoE. The patients followed a milk-free diet for nine months, then re-introduced milk into their diet for the next two months. At the end of the study, almost half of those wearing the patch had fewer EoE symptoms, including less inflammation down to the normal range when they underwent an endoscopy compared to none in the placebo group.

Quick thoughts:

“This study shows great promise for an immunotherapy that aims to desensitize children to milk,” Dr. Spergel said.

What’s next:

Dr. Spergel’s next step in this line of research is to launch a much larger study to confirm their results. Since there is no cure for EoE, the larger study would be the first strategy to treat the underlying cause of the disease.

Where the study was published:

The study appeared online in the journal Clinical Gastroenterology and Hepatology.

Who helped fund the study:

DBV Technologies funded the study but had no role in analysis or interpretation of data.

Where to learn more:

Learn more about this study in this CHOP press release.

The finding:

A team of researchers in the Division of Hematology at Children’s Hospital of Philadelphia further refined how a treatment currently used on an urgent basis to control bleeding in hemophilia patients holds promise as a preventive treatment as well. Their animal study may set the stage for a new therapy for a subset of patients with hemophilia who develop antibodies to the standard maintenance treatment and then require on-demand “bypass” therapy.

Why it matters:

“Patients who develop antibodies to the coagulation factors usually prescribed for hemophilia have a complicated treatment,” said study leader Paris Margaritis, DPhil. “A different factor, called coagulation factor VIIa, restores blood clotting when given after a bleed occurs, but we don’t know the target level of circulating factor VIIa that would prevent bleeds before they start. Our new preclinical results are the first to show target levels that could act prophylactically.”

Who conducted the study:

Dr. Margaritis, a hematology researcher in the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at CHOP, led the study.

How they did it:

Dr. Margaritis and his team have extensively investigated gene transfer in animal models, finding that delivering corrective DNA carrying the coded instructions produced factor VIIa and reduced bleeding episodes. Building upon those studies, the study team worked with a hemophilia A rat model and used adeno-associated virus as a vector to deliver a rat factor VIIa gene, which expressed steadily in the bloodstream, simulating prophylaxis. Hemophilia A rats that had a specific level of factor VIIa in their bloodstream experienced reduced bleeding, and those with a higher level, had no bleeds whatsoever.

Quick thoughts:

“For the first time, we have threshold levels of factor VIIa for prophylactic use,” Dr. Margaritis said. “Because factor VIIa bypasses the need for factor VIII or IX, it should work in both hemophilia A and hemophilia B. Furthermore, it works whether or not inhibitors are present in the blood.”

What’s next:

The next steps are to translate threshold levels in rats to levels in humans and then leverage that information to test the approach in clinical trials.

Where the study was published:

The study appeared in the journal Blood Advances.

Who helped fund the study:

Novo Nordisk A/S and the National Institutes of Health provided funding for the study.

Where to learn more:

Learn more about this research in this CHOP press release.

The finding:

New pre-clinical findings from extensive cell and animal studies suggest that a drug already approved by the U.S. Food and Drug Administration for a rare kidney disease could potentially benefit patients with some primary mitochondrial disorders — complex, multi-system conditions with severe energy deficiency for which no proven effective treatments exist.

Why it matters:

Because pathogenic variants in over 350 different genes across both nuclear and mitochondrial DNA genomes are now recognized to cause mitochondrial diseases, these disorders are collectively common and highly complex. They typically cause 16 or more major symptoms in each patient, affecting multiple organs and body systems. The current study found therapeutic potential for this repurposed drug in primary mitochondrial disease, based on evidence for neuroprotection in two different animal model species as well as studies in human patient cells.

Who conducted the study:

Marni J. Falk, MD, who serves as executive director of the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia, led the study.

How they did it:

Dr. Falk and her colleagues have been evaluating a variety of drug candidates for use as possible treatments for mitochondrial RC diseases. For example, they recently found that an antioxidant called NAC (short for N-acetylcysteine) that crosses into the brain showed encouraging pre-clinical results in animal studies. Because cysteamine bitartrate, which is currently approved by the FDA to treat a rare kidney disorder called nephropathic cystinosis, was thought to possibly act similarly to NAC on some biochemical pathways, Dr. Falk’s team performed their current pre-clinical research study.

They specifically tested the hypothesis that cysteamine bitartrate would increase synthesis of glutathione, a potent antioxidant enzyme that humans and animals naturally produce from amino acids including cysteine — which can be generated from cysteamine bitartrate to scavenge free radicals. The team learned that cysteamine bitartrate did not, in fact, increase total glutathione levels in their experiments. Nonetheless, Dr. Falk and her team found it had beneficial health effects that appear to result from different mechanisms than they had anticipated.

They found therapeutic potential for cysteamine bitartrate in mitochondrial disease, based on evidence for significant neuroprotection in two different zebrafish vertebrate animal models, improved mitochondrial function and reduced mitochondrial oxidative stress in C. elegans worm in vertebrate animal models, and improved survival of mitochondrial disease patient cells when stressed. However, they also showed that the drug has a narrow therapeutic window — even relatively small increases in dosage could dramatically increase free radical production and were toxic in diverse laboratory animals and human cells, implying that dosages would need to be very carefully controlled if cysteamine bitartrate eventually were to become a precision medicine treatment option for mitochondrial disease patients.

Quick thoughts:

“A better understanding of each mitochondrial disease patient’s level of oxidative stress and defenses, tested in carefully designed clinical trials to determine the health benefits or risks of candidate therapies from preclinical animal studies, will enable a precision mitochondrial medicine approach to select optimal therapies including antioxidants, and their specific doses, to use to improve health resiliency and outcomes for each patient,” Dr. Falk said.

What’s next:

Future clinical research is needed to explore whether the drug, cysteamine bitartrate, will meaningfully benefit patients. New clinical diagnostic tests, outcome measure assessments, and advanced data integration and visualization systems to facilitate this process are under development in CHOP's Mitochondrial Medicine Frontier Program.

Where the study was published:

The study appeared in advance online and in print in the journal Human Molecular Genetics.

Who helped fund the study:

The National Institutes of Health, Raptor Pharmaceuticals, the Juliet’s Cure Mitochondrial Disease Research Fund, and the Will Woleben Research Fund funded this research study.

Where to learn more:

Learn more about this study in this CHOP press release.

The finding:

A team of Children’s Hospital of Philadelphia researchers found that specialized lung cells appear in the developing fetus much earlier than scientists previously thought. Their study reported how cells that become alveoli begin their specialized roles very early in prenatal life.

Why it matters:

Investigating the fetal signaling pathways active in this biological event may offer future opportunities to treat lung damage caused by prematurity and other lung injuries.

Who conducted the study:

David B. Frank, MD, PhD, a pediatric cardiologist at CHOP and a member of the Penn Center for Pulmonary Biology and the Penn Cardiovascular Institute, co-led the study with colleagues from the University of Pennsylvania.

How they did it:

The research team focused on the basic function of respiration — the exchange of oxygen and carbon dioxide within alveolar type 1 and type 2 cells. They used single-cell RNA sequencing analysis, protein expression studies, and a new lineage-tracing tool to reveal details of early lung formation in a fetal mouse model.

They found that the specification of alveolar cells begins simultaneously with early lung formation, as cells in the developing embryo begin to move apart and branch out into specialized structures such as airways and alveoli. Many lung cells commit themselves to “cell fates,” their specialized roles, during branching morphogenesis, which occurs before the formation of the sac-shaped structure that becomes the lung alveolus.

Quick thoughts:

“This cell specification begins remarkably early in lung development, and it progressively seeds the premature lung alveolus throughout the fetus’s gestation,” Dr. Frank said. “The early presence of these specialized alveolar cells may account for the fact that a minority of extremely premature human babies survive even with underdeveloped lungs.”

What’s next:

The research team plans to further explore how their findings could eventually contribute to future treatments. A better understanding of lung development could lead to potential tools in regenerative medicine, perhaps by manipulating key signaling pathways or novel progenitor cell targets to grow new lung tissue after injury from prematurity or from acquired lung disease.

Where the study was published:

The study appeared in the journal Proceedings of the National Academy of Sciences.

Who helped fund the study:

The National Institutes of Health, the Parker B. Francis Foundation, the Pulmonary Hypertension Association, Burroughs Wellcome, the National Science Foundation, and the Gilead Research Scholars Foundation provided funding for the study.

Where to learn more:

Learn more about this study in this CHOP press release.