A boy living with a rare genetic condition was almost "out of options" when a genetically engineered zebrafish showed a way to save his life—a medical feat that his doctors say demonstrates precision medicine's potential to treat disorders beyond cancer, Sharon Begley reported for STAT News, according to an article published in Nature.

Daniel's symptoms

In an article published Monday in Nature, doctors shared the boy's story. The boy, Daniel, first started experiencing the symptoms of his condition when he was 10. His legs started to swell, he had trouble breathing, and though he'd once been an avid soccer player, he could no longer exercise, according to the Nature article.

When Daniel was 12, he was sent to Children's Hospital of Philadelphia (CHOP) where he was given palliative treatment that involved cauterizing lymphatic vessels and sirolimus, an immune-suppressing drug. "But nothing helped for long, and sirolimus didn't help at all," Begley writes. In fact, by the time Daniel reached CHOP, his lungs were filled with so much fluid that he needed an oxygen tank.

The boy "was quickly running out of options," Begley writes.

Hakon Hakonarson, a pediatric lung specialist and director of the Center for Applied Genomics at CHOP, said, "He got worse and worse and worse." Hakonarson continued, "He was going to die."

The zebrafish that saved his life

Hakonarson, one of the authors of the article, decided that looking for the genetic root of Daniel's problem was the boy's last chance, Begley reports. So, Hakonarson and his colleagues sequenced part of Daniel's genome. The researchers found the genes that are usually linked to lymphatic disorders looked normal. But ARAF, a gene that lives on the X chromosome that creates the enzyme kinase, did not.

ARAF mutations had never been linked to lymphatic disorders in the past, but the researchers decided to test it and see if it could be related to Daniel's illness.

To determine this, they genetically engineered zebrafish embryos to have the mutation. After just a few days, the fish developed lymphatic systems with "lymphatic vessels that grew and grew, just like Daniel's," Begley writes, which proved that the "mutation causes overgrowth," according to Hakonarson.

To find a treatment for the overgrowth, the researchers tested 10 different MEK inhibitor drugs on the zebrafish, and found that trametinib, a melanoma drug sold by Novartis, was the best treatment.

Before treating Daniel, Hakonarson and his team sought approval from FDA. "We did not want to take the chance of giving a toxic, adult drug to a child," he said.

Once approved, Daniel was put on the treatment. According to the researchers, his breathing improved within two months and within three months, he no longer needed supplemental oxygen. Eventually, results of an MRI showed that Daniel's lymphatic vessels had "reshaped themselves into something close to normal," Begley writes. "It was the first time a drug had remodeled an entire organ system."

Implications

The success of the treatment serves as an example that precision medicine can treat illnesses beyond cancer, according to authors.

Similar to lung cancer, for instance, Daniel's illness could have been caused by one of many possible mutations, each with their own "biological road," Begley reports. The way to treat the disease is with "a drug that targets the right road can stop the disease," Begley writes.

V. Reid Sutton of Texas Children's Hospital said the "approach definitely could be used clinically,” to treat lymphatic disorders, which impact one out of 4,000 newborns each year. "It suggests that we should do this sort of genetic testing to identify where in the biological pathway the problem is and try to find a drug that targets it."

Researchers not involved in the study, however, said that this one success should not be considered proof that precision medicine can always treat rare lymphatic disorders. They noted that research involving more patients for a longer amount of time is needed.

Still, Matt Warman, a medical geneticist at Boston Children's Hospital, said that the researchers "have performed a service to patients affected by these distressing disorders. As we identify additional causes [of lymphatic anomalies], we should be able to do more mutation-specific therapies," he said (Begley, STAT News, 7/1).