Lung Repair, License Suspensions, Lymphatics Disorder, Friedreich’s Ataxia, Racism

limjr [at] email.chop.edu (By Jillian Rose Lim)

Driver’s license suspension disparities, the discovery of a “druggable” cellular pathway, and a declaration to support equitable healthcare are all top of mind this week in our research highlights. Learn how our researchers identified a target to stimulate tissue repair in lung disease, reported disparities in the prevalence of non-driving-related license suspensions, treated a severe lymphatic disorder using precision medicine, and joined a network of fellow institutions in a statement to address the impact of structural racism in our communities.

Signaling Pathway Stimulates Lung Tissue Repair, Points to Treatment for COVID Complications

The discovery of a cellular pathway involved in lung tissue regeneration by researchers at CHOP and the University of Pennsylvania could lead to new treatments for patients with lung disease, including complications of COVID-19 like acute respiratory distress syndrome (ARDS). In a paper published in Nature Cell Biology, the team describe their identification of a signaling pathway that can be targeted to stimulate lung regeneration. The team also identified a naturally-occurring compound, 7,8-Dihydroflavone (7,8-DHF), that targeted a receptor in the pathway and prompted the acceleration of tissue repair in animal models of lung injury.

“These findings provide identification of precision targets and thus allow for rational development of therapeutic interventions for lung disease caused by COVID-19 and other illnesses,” said senior author G. Scott Worthen, MD, physician-scientist in the Division of Neonatology. The study’s first author, Andrew J. Paris, MD, instructor of Medicine at Penn, added that “based on the results of this study, we think 7,8-DHF is an excellent candidate for entering clinical trials for patients with lung diseases.”

No drugs to date have been developed specifically to treat ARDS in COVID-19 patients, so finding such pathways involved in tissue regeneration is key to developing effective therapies. In this study, the researchers elucidated on previous research that shows cells called type II alveolar pneumocytes (AT2) play a role in lung repair. Dr. Worthen and his team explored what changes occurred in AT2 cells after disease-related injury to promote repair, and how regenerating AT2 cells might influence interactions with nearby cells also important in tissue repair, mesenchymal cells.

Learn more in the press release.

More Than 90 Percent of License Suspensions Not Related to Traffic Safety

New research utilizing data from the New Jersey Safety and Health Outcomes Data Warehouse shows that the majority of license suspensions are from non-driving related events, such as failure to pay a fine, according to a study team from CHOP and Brown University. Furthermore, the study published in the Journal of Transport & Health documents widespread disparities in the prevalence of these suspensions, finding that they disproportionately affect those living in low-income communities and communities with a greater percentage of Black and Hispanic residents.

Among more than 7.6 million licensed NJ drivers, 5.5 percent of the state’s driving population had a suspended license in 2018. Of those with suspended licenses, 91 percent were given for a non-driving-related event. The prevalence of these non-driving-related suspensions was seven times greater in the lowest income neighborhoods versus the highest income neighborhoods, and five times greater in neighborhoods with the highest percentage of Black and Hispanic residents versus the lowest percentage of Black and Hispanic residents.

“What is particularly concerning is that the communities most burdened by license suspensions are already facing heightened barriers to employment and healthcare,” says Allison E. Curry, PhD, MPH, senior co-author of the study and a senior scientist and director of Epidemiology and at the Center for Injury Research and Prevention. “We’re also conducting a complementary study to learn firsthand from individuals whose licenses were suspended about how this transportation barrier affects their health and well-being.”

Read more about this work in the press release. Learn more about the NJ-SHO on Cornerstone.

Precision Medicine Reverses Severe Lymphatic Disorder in Patient

In Kaposiform lymphangiomatosis (KLA), a complex lymphatic disorder, lymphatic vessels around a patient’s heart and lung leak fluid, causing breathing difficulties, infections, and sometimes death. For one patient with KLA, Brenna, who is described in a recent EMBO Molecular Medicine paper published by CHOP researchers, the disorder can involve trying of a variety of therapies with symptoms continuing to persist. In the paper, however, the researchers describe a success story for Brenna: Using genetic sequencing and targeted treatment, they were able to completely resolve her symptoms and fully remodel her lymphatic system.

The researchers used a drug called trametinib, a mitogen-activated protein kinase (MEK) inhibitor, previously used in another patient with a different severe lymphatic disorder and a mutation in the NRAS gene. Since many patients with KLA share this mutation, the team wondered if trametinib might improve Brenna’s rapidly deteriorating condition. Genetic sequencing showed Brenna did not, in fact, harbor a NRAS mutation, but confirmed she had a mutation in CBL, a gene that operates along the same pathway. Mutations along this particular pathway result in the overproduction of MEK, prompting the uncontrolled proliferation of lymphatic vessels. MEK inhibitors like trametinib, however, can bring MEK production under control.

Within four weeks of starting a low trametinib dose, Brenna’s shortness of breath, coughing, and difficulty breathing while lying flat disappeared. At 20-years-old, Brenna continues to take a dose of trametinib, and her symptoms are kept at bay. In follow-up tests, her overabundant lymph vessels remodeled themselves and now behave normally.

“The resolution of lung disease with lymphatic remodeling is remarkable and potentially should change how we evaluate and treat lung disease in this patient population,” said first author Jessica B. Foster, MD, physician in the Division of Oncology. “These results offer hope to other patients with lymphatic-induced lung disease and warrant further investigation.”

Learn more about Brenna’s story and the targeted treatment in the press release.

CHOP Joins Worldwide Consortium to Study Biomarkers, Natural History for Friedreich’s Ataxia

Friedreich’s Ataxia (FA) is a rare neurogenetic condition that causes progressive nervous system damage and movement problems, often beginning in childhood and leading to impaired muscle coordination over time. CHOP joined the Friedreich’s Ataxia Research Alliance (FARA) alongside several institutions in the most extensive worldwide neuroimaging study in FA to date, TRACK-FA. TRACK-FA will track brain spinal cord changes in individuals with FA, with 200 children and adults expected to enroll in the study. The study will explore the natural disease history of FA and aims to determine biomarkers that could help in the development of new therapies and the creation of a comprehensive database for researchers around the world.

“Together, we aim to identify and validate neuroimaging biomarkers indexing disease progression in FA; an important first step toward developing a treatment for this rare and debilitating disease,” said William Gaetz, PhD, research scientist in the Department of Radiology, in a press release.

CHOP Joins U.S. Health Systems Network to Declare: Racism is a Public Health Crisis

In a collaborative commitment to take action and address the impact of structural racism in our communities, CHOP joined its fellow members of the Healthcare Anchor Network in the publication of a statement, “Racism is a Public Health Crisis.” The statement comes from the 39 health systems in 45 U.S. states that are part of the Healthcare Anchor Network, a national collaboration of leading healthcare systems.

In the statement, the network writes: “Our society only truly thrives when everyone has an opportunity to succeed and live a healthy life. We are committed to moving forward together. By harnessing the collective strengths of our organizations, we will help serve our communities as agents of change.”

Gilbert Davis, vice president and chief diversity officer at CHOP, commented in a CHOP press release: “No one individual or institution can do this alone, and we are committed to listening to our neighbors of color and implementing initiatives that will help to eradicate all forms of discrimination. CHOP is committed to being intentional, and we will partner with others in the community to address the social injustice and systemic racism that contribute to disparity of care across our region.”

Learn more in the press release and read the full statement online.

ICYMI

Catch up on our headlines from our Sept. 25 In the News:

• Handheld Device Facilitates Concussion Diagnosis in Teen Athletes
• Most Mass Shootings Occur Within a Mile of Places Children Gather
• Modern Techniques Assist in Diagnosing Lymphatic Disorders in Infants
• Key Genetic Differences Observed in ADHD Between African American, European Ancestries
• COVID-19 Incidence May Resurge With Cooler Weather
• Lab Features May Distinguish MIS-C From Kawasaki Disease, Mild Inflammation

Keep up with our news, stories, and updates in real time by following us on Twitter, Facebook, LinkedIn, or Instagram. Or subscribe to our newsletter to get an email sent every other Friday by signing up here.