Children’s Hospital of Philadelphia (CHOP) recently tailored experimental precision therapy under intensive conditions and in real-time to save a young boy’s life. Suffering from a rare, complex genetic condition, the boy owes his life to Zebrafish. Zebrafish is frequently used in preclinical research for studies concerning genetics, development and disease reports Stat News’ Sharon Begley. We suggest that the doctors who made this possible are heroes who deserve recognition.

TrialSite News breaks down the events.

A Young Boy with A Rare Lymphatic Condition

The boy’s name is Daniel. When he was 12, the family took him to CHOP due to urgent health conditions. At age 10 he first encountered what would become a life and death situation. While playing soccer the conditions emerged, resulting in swollen legs and breathing difficulties with such intensity and severity that exercise was not possible. Daniel was treated at a local Virginia hospital which identified lymphatic fluid buildup around the heart. The provider drained the area only to find that the lymphatic fluid continued to leak in. Suddenly the matter took a more severe turn.

Situation Escalated—Transfer to CHOP

Daniel was transferred to CHOP where he received immediate palliative treatment including the cauterization of lymphatic vessels and sirolimus, an immune-suppressing drug (rapamycin) that has been helpful for certain patients afflicted with lymphatic diseases but not others, reports Ms. Begley. Nothing helped Daniel and his condition worsened by age 12.

Nothing Worked—From Bad to Imminent Death

His lungs became so full that he needed an extra oxygen tank to breathe, and death appeared imminent. The situation became so dire that perhaps only a miracle would save Daniel from a premature death.

A Rare Complex Genetic Condition

Daniel faced a condition that only about 1 in 4,000 newborns ever face. Lymphatic vessels proliferate out of control and consequently leak ever more fluid into the lungs and other vital organs.

The CHOP Team Moves into Action

As published in their study titled “ARAF Recurrent Mutation Causes Central Conducting Lymphatic Anomaly Treatable with a MEK Inhibitor” Daniel was in grave danger. Dr. Hakon Hakonarson, his physician at CHOP said, “He was going to die.”  The CHOP team had no time to waste; they had to immediately come up with a treatment to keep this young boy alive.

Getting to the Root of the Problem

As reported in the study and by Begley, the CHOP team knew they must get to the root of Daniel’s condition. The CHOP team had to sequence his genome—part of the genome that produces proteins. They rapidly worked to uncover a genetic ARAF defect. As it turns out, ARAF produces an enzyme that is known as a “kinase that adds dangly molecules to a cell’s proteins.” If this goes out of control, a cell can become cancerous, or in the case of Daniel’s condition, “sprout lymphatic vessels like creepers from a neglected patch of ivy.” Apparently, this genetic mutation was just a random back luck draw—neither of Daniel’s parents had such a mutation.

Real Time CHOP Miracle Work: Precision Discovery, Clinical Research as a Treatment Option

Working with an intense urgency, the CHOP team leveraged the uncovered genetic knowledge: the identified mutation was ARAF. Team members were mobilized to engineer Daniel’s exact mutation into zebrafish to simulate preclinical drug development conditions. Thereafter, the CHOP team had to observe the fish actually developing a piscine version of the disease.

Once the same condition was developed in the zebrafish, the team rapidly tested multiple drugs on the fish to determine what could at least deter, if not stop, the symptoms. Thankfully, the CHOP team discovered that one drug stopped the vessels expansive growth. With no time to waste, the team had to secure emergency approvals from federal authorities to use the substance, a MEK Inhibitor, in an investigational manner. This essentially represented a real-time clinical trial with a young boy’s life at stake. CHOP received expedited federal approval.

A Precision-based Outcome

The drug that worked was Novartis’ Trametinib (Mekinist). The mutation that caused Daniel’s illness was much like a cancer mutation—triggering a lymphatic anomaly with potentially deadly consequences. Other physicians believe the CHOP team has created a compelling case for applying genetic techniques to lymphatic disorders. For example, the Texas Children’s Hospital sees about 50 similar children a year and lives could be saved.

Zebrafish to the Rescue

Daniel lived thanks to the ability of researchers to utilize zebrafish, tiny creatures that are now a standard go-to-animal for preclinical studies. The CHOP team was able to develop a lymphatic system in the zebrafish within five days. According to CHOP team members, zebrafish develop conditions with “lightening fast” speed. In this case, they developed the ARAF mutation in a quarter-inch length zebrafish and the lymphatic vessels materialized quickly. Based on the real time investigation with zebrafish, the CHOP team had proven that the ARAF mutation causes overgrowth of lymphatic vessels.

Conclusion

Daniel is healthy again. Stat News reports he is a normal kid again—playing basketball and soccer and bike riding. Most importantly, he survived and has a long life ahead now. The CHOP team led by Hakonarson and Seiler pulled off a miraculous treatment. Time was not on their side and there were seemingly no options left. State News reports that other experts caution that this example of a real time miracle is not a guarantee it can be repeated. Obviously, one success doesn’t mean that exome sequencing and targeted therapy will result in similar outcomes when it comes to rare lymphatic anomalies. Nonetheless, Dr. Matt Warman, a medical geneticist at Boston Children’s Hospital noted, “this is the first paper to implicate ARAF in vascular malformation and to demonstrate MEK inhibition may be effective.” There are other clinicians presently treating other patients with mutation-driven vascular malformations with MEK inhibitors.

Lead Physician for Daniel’s Care Team

Dr. Hakon Hakonarson, lung specialist and director of the Center for Applied Genomics at Children’s Hospital of Philadelphia (CHOP)

Christoph Seiler, Director Zebrafish Core, Children’s Hospital of Philadelphia

Source: Nature

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