2019 Scientific Year in Review
A number of research studies were published in 2019 that will benefit patients around the world with complex lymphatic anomalies (CLAs).
Below is information about about some key projects that were made possible through the financial support of patients, their families, friends of the LGDA and its research partner, the Lymphatic Malformation Institute (LMI); and the willingness of patients to participate in research:
ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor
Led by a team of researchers at the Children’s Hospital of Philadelphia (CHOP), genetic testing called whole exome sequencing (WES) was undertaken in a series of patients, identifying a mutation in a gene known as ARAF in two unrelated patients with complicated lymphatic anomalies. One patient had been diagnosed with central conducting lymphatic anomaly (CCLA) and the other was diagnosed with lymphangiomatosis.
The researchers were able to produce zebrafish with the same mutation so that they exhibited the lymphatic anomaly. The zebrafish given trametinib, a drug that inhibits the activity of one of a chain of proteins called MEK, showed remarkable improvement.
Ultimately, the patient with CCLA was treated with trametinib and showed dramatic improvement in pulmonary function and a return to near normal daily activity. The other patient unfortunately died in 2017 of complications of lymphangiomatosis before any use of trametinib could be undertaken.
Ongoing recruitment for the study, one channel of which was in partnership with the LGDA Patient Registry, led to the enrollment of 43 additional patients and the identification of 7 additional mutations.
Somatic activating mutations in PIK3CA cause GLA
This project undertaken by the team at La Paz Children’s Hospital in Madrid, Spain, collected tissue samples from nine patients with generalized lymphatic anomaly (GLA), formerly known as lymphangiomatosis. They identified mutations in the PIK3CA gene in five of the nine patients with GLA. These activating PIK3CA mutations are known to cause hyperactivity within the mTOR pathway. The paper describes the lymphatic hyperplasia and dysfunction in mice having PIK3CA mutations and the effectiveness of the drug rapamycin (sirolimus) in treating both mice and human patients with GLA.
All patients treated with rapamycin reported a reduction in pain. Additionally, this is the first study to report bone loss associated with PIK3CA mutations. While there are numerous positive findings from this study, the paper makes clear that controlled clinical trials are needed to develop specific treatment protocols for GLA.
This work was funded by the LGDA’s research partner The Lymphatic Malformation Institute (LMI).
Mechanisms of Bone Loss in GSD
In 2016, Andrea Del Fattore, PhD, and Andrea Bartuli, MD, and their team at Bambino Gesù Children’s Hospital, in Rome, Italy, were awarded funds raised for a research study through the LGDA’s and LMI’s participation in the Million Dollar Bike Ride (MDBR). The goal of the research was to help better understand the mechanisms which lead to bone loss in GSD. The findings suggest that the massive bone loss and vessel proliferation seen in GSD may be the result of independent alterations by bone cells in cooperation with systemic factors.
Julie Blatt, MD, Awarded $62K through Million Dollar Bike Ride
We are pleased to announce the awarding of a grant of funds raised through the 2019 Million Dollar Bike Ride to Julie Blatt, MD. Through this pilot study, Dr. Blatt and her team seek to develop a model with which to test the repurposing of antiangiogenic drugs in treating lymphatic malformations.
Dr. Blatt is Professor of Pediatrics, with tenure, Division of Pediatric Hematology Oncology, at the University of North Carolina, Chapel Hill.
The funds awarded through this grant were raised through the efforts of all those who participated in the bike ride and made donations to support Team LGDA & LMI. Those donations were matched by the MDBR and the funds are distributed through the Orphan Disease Center at University of Pennsylvania, which hosts the event each year.