Rare Daily Staff

A team of specialists at Children’s Hospital of Philadelphia demonstrated the potential to screen individual patients with rare diseases to repurpose existing therapies that might best be used to treat their condition in a case where they saved the life of a 10-year-old boy.

The study team published their findings online in Nature Medicine.

The patient, Daniel, was a competitive soccer player and runner when he first came to his local hospital in Virginia with swelling in his lower body, shortness of breath and exercise intolerance caused by a buildup of lymphatic fluid around his heart. Doctors drained the fluid, but it continued to accumulate. He was transferred to Children’s Hospital of Philadelphia (CHOP) for further evaluation.

At CHOP, researchers identified a gene mutation responsible for his deteriorating rare condition. Daniel had been born with a complex defect that disrupted the circulation of lymphatic fluid throughout his body.

A geneticist and a pediatric cardiologist with expertise in lymphatic disorders co-led a team effort to translate knowledge of the affected biological pathway into a treatment, repurposing an existing drug that caused the abnormal lymphatic system to remodel itself. This result may form the basis of a new therapy for this type of defective lymphatic circulation.

“This case is a dramatic example of implementing a precision medicine treatment for a life-threatening rare disease,” said study leader Hakon Hakonarson, director of the Center for Applied Genomics at CHOP. “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.”

Hakonarson collaborated with pediatric cardiologist Yoav Dori, from the innovative Center for Lymphatic Imaging and Interventions, based at CHOP. Daniel had a lymphatic conduction disorder known as a central conducting lymphatic anomaly. The gene mutation drove uncontrolled proliferation of abnormal lymphatic vessels, leading to leak of lymphatic fluid, edema, and respiratory difficulties.

“Because we were able to repurpose an existing drug to block the signals causing the dysregulated growth, we caused our patient’s lymphatic channels to reshape themselves into a more normal anatomy and function, and dramatically improved his condition,” said Dori.

The lymphatic system interacts with the cardiovascular system, absorbing and returning fluid from tissues back to the venous circulation. As lymphatic fluid circulates through the body, it has a crucial role in immune function, as well as fat and protein transport.

Abnormal lymphatic flow, which often goes undiagnosed, may cause fluid accumulation in the chest, abdomen or other tissues, leading to respiratory distress, abdominal swelling, and severe swelling of the limbs or tissues. The lymphatics team blocked the abnormal flow and used minimally invasive methods to initially stabilize the problem, but the fluid buildup reoccurred and worsened over the next two years.

Daniel’s respiratory problems and swelling worsened, despite a variety of minimally invasive and surgical interventions. Sirolimus, a drug commonly used in lymphatic conditions, did not work. The care team was running out of options and Daniel’s condition continued to deteriorate.

Hakonarson team performed whole-exome sequencing on Daniel’s DNA with the aim of identifying a specific genetic cause for his condition. The team also did whole-exome sequencing on DNA from an unrelated young adult patient, from another center, with a severe lymphatic condition.

In both cases, the sequencing identified a previously undiscovered gain-of-function mutation in the ARAF gene. The adult patient died from this life-threatening disease before the subsequent experimental treatment became available.

The researchers explored the function of the ARAF mutation by inserting it into the embryos of zebrafish, an animal frequently used to model genetic diseases. The zebrafish then developed similar abnormal lymphatic channels. The researchers then used a drug called a MEK inhibitor known to act on biological pathways affected by ARAF. The drug “rescued” the structural defect in the zebrafish, causing them to develop normal lymphatic vessels.

MEK inhibitors are typically approved for use in patients with certain cancers. Based on their zebrafish results, Hakonarson and Dori consulted with Jean Belasco from the CHOP oncology team, who is a leading clinician in vascular anomalies, and a study co-author. Belasco obtained compassionate permission from the U.S Food and Drug Administration to use a MEK inhibitor called trametinib in Daniel.

Within two months after starting the experimental treatment, Daniel’s breathing improved. Three months after starting the treatment, he had reduced fluid retention and was able to cut back on supplemental oxygen, start breathing room air, and begin more physical activity. An MRI showed that his lymphatic vessels were remodeling themselves. He was able to stop using supplemental oxygen and transition to breathing room air. The heavy swelling in Daniel’s legs gradually disappeared.

Now 14 years old, Daniel has been able to resume many normal activities, such as riding his bicycle, playing basketball, taking up weight training, and helping to coach soccer camps.

Dori and Hakonarson said that this research is the first real evidence for complete remodeling of an entire organ system by a drug and offers hope for many patients with similar lymphatic flow disorders.

“Our work,” they wrote, “exemplifies how genetic discoveries can impact disease classification and uncover novel biological and life-saving treatments.”

Photo: Hakon Hakonarson, director of the Center for Applied Genomics at CHOP

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