A study team at Children’s Hospital of Philadelphia discovered a gain-of-function mutation in the ARAF gene causing a life-threatening rare disease known as central conducting lymphatic anomaly that disrupts circulation of lymphatic fluid. They also identified an existing drug that acts on biological pathways affected by ARAF. The experimental treatment had dramatic results for a young boy with the disease who had worsening respiratory and swelling problems. The drug blocked the signals causing the dysregulated growth and abnormal lymphatic flow, prompting his lymphatic channels to reshape themselves into more normal anatomy and function.
Why it matters:
The study’s findings may form the basis of a new therapy for this type of defective lymphatic circulation. This research is the first real evidence for complete remodeling of an entire organ system by a drug, and it offers hope for many patients with similar lymphatic flow disorders.
Who conducted the study:
Study leader Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP, collaborated with pediatric cardiologist Yoav Dori, MD, PhD, of the Center for Lymphatic Imaging and Interventions at CHOP. Jean Belasco, MD, from the CHOP Oncology team co-authored the study. They worked with a preteen boy from Virginia and his family to test the experimental therapy with compassionate use permission from the Food and Drug Administration.
How they did it:
The study team performed whole-exome sequencing on DNA from the young boy and from an unrelated young adult patient with a severe lymphatic condition from another center who died prior to completion of the study. In both cases, the sequencing identified a previously undiscovered mutation in the ARAF gene.
The researchers worked with zebrafish models to explore how the responsible gene mutation disrupted lymphatic channels. Next, they demonstrated that a drug called a MEK inhibitor, known to act on biological pathways affected by ARAF, “rescued” the structural defect in the zebrafish, causing them to develop normal lymphatic vessels.
These results supported the physicians’ request to use a MEK inhibitor called trametinib (a chemotherapy drug) in the CHOP patient. After three months of treatment, the boy showed significant improvements in his breathing and reduced fluid retention, and an MRI showed that his lymphatic vessels were remodeling themselves.
“This case is a dramatic example of implementing a precision medicine treatment for a life-threatening rare disease,” Dr. Hakonarson said. “We discovered a causative gene mutation in two patients, identified an existing drug that acts on that gene’s pathway, showed that the drug relieves the condition in lab animals, and then successfully treated the original patient.”
Based on this work, CHOP is expanding an existing program in complex vascular anomalies that investigates the underlying genetic mutations that impair normal development of blood or lymphatic vessels. “All lymphatics patients are now also seen by our genomics team,” Dr. Hakonarson said.
Where the study was published:
The study appeared in Nature Medicine.
Where to learn more:
Learn more details about this mutation discovery in a press release and in news coverage by the Philadelphia Inquirer. Stay tuned for a Cornerstone post about CHOP’s Complex Vascular Anomalies Program Frontier Program.