How to save a life

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Science Translational Medicine  24 Jul 2019:
Vol. 11, Issue 502, eaay3578
DOI: 10.1126/scitranslmed.aay3578


A zebrafish model was used to identify successful therapy for a child with lymphatic anomaly.

Precision medicine—the concept of using molecular insight to identify patient-specific treatments—offers hope for patients with rare deadly diseases. However, in the vast majority of cases, the hype has far exceeded the hope. A recent report by Li et al. is a welcome exception.

This report describes the case of a 12-year-old boy who presented to the Children’s Hospital of Philadelphia with a rare condition called central conducting lymphatic anomaly. This disease is characterized by accumulation of lymphatic fluid around vital organs, usually leading to death. This particular case was resistant to standard treatment with sirolimus. This patient did not have any of the typical mutations for lymphatic anomaly, but exome sequencing revealed a c.640T>C:p.S214P mutation in the ARAF gene. Because the same ARAF mutation was noted in a previous patient who passed away from lymphatic anomaly, the team decided to evaluate its functional effect. Based on sequence homology with other RAF family proteins, this mutation was predicted to interfere with the negative regulation of ARAF by 14-3-3. Indeed, human dermal lymphatic cells transfected with mutant ARAF S214P showed increased signaling in the MEK/ERK pathway downstream of ARAF. Mutant ARAF also caused abnormal growth of these lymphatic cells in vitro. Promisingly, these changes were reversed by addition of a MEK inhibitor trametinib. This drug, which targets signaling downstream of ARAF, was hitherto used only for cancer treatment.

Before using these in vitro findings to decide on a treatment strategy, the researchers confirmed their observations in a living organism. They chose the zebrafish, which offer the advantage of rapid organ development. The researchers were able to thus visualize the effects of mutant ARAF S214P on the zebrafish lymphatic system and confirm that treatment with trametinib reversed these changes. Given the lack of conventional treatment options, ethical board review allowed treatment of this dying child with trametinib. From being bedridden and breathless, the patient returned to near normal activity within a year.

A similar strategy may not work with all mutations causing lymphatic anomaly. However, this case illustrates a path forward for the future of translational medicine. What is remarkable here is that the key components of the translational medicine pipeline—including molecular profiling of the disease, identification of recurrent events, and understanding of functional effects—were all coordinated in a turnaround time compatible with treating and saving a patient. Yet again, hope remains for precision medicine.

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