A team of researchers, led by Columbia University Vagelos College of Physicians and Surgeons, has been awarded an $8.7 million contract from the Advanced Research Projects Agency for Health (ARPA-H). This two-year contract is specifically designated for the creation of genetic tests aimed at accelerating the diagnosis of patients born with lymphatic system defects.
Project Goals and Leadership
The project, named CLARUM (Comprehensive Lymphatic Anomaly Revealing and Understanding Genomics), seeks to identify genes causing lymphatic anomalies.
CLARUM's primary goal is to facilitate the development of new clinical tests, improve treatments, and potentially save lives by identifying genes that cause lymphatic anomalies.
Carrie Shawber, PhD, associate professor of reproductive sciences at VP&S, serves as the principal investigator for the CLARUM project. Dr. Shawber leads this critical initiative at Columbia University.
Key Collaborators
CLARUM involves collaboration with several institutions: Arkansas Children's Hospital, Boston Children's Hospital, the Broad Institute, Children's Hospital of Philadelphia (CHOP), City St. George's University of London, and NYU Langone Health.
Funding and the Lymphatic System
The funding is provided through the ARPA-H LIGHT (Lymphatic Imaging, Genomics, and pHenotyping Technologies) program. This program is dedicated to developing novel diagnostic approaches to enhance understanding of the lymphatic system's role in health and improve patient outcomes.
The lymphatic system is a complex network of vessels, ducts, and nodes crucial for the body's fluid movement, maintaining tissue fluid levels, and transporting fats, hormones, and immune cells.
Beyond fluid regulation, the lymphatic system plays a vital role in preventing and regenerating organ damage.
The Challenge: Diagnosing Congenital Lymphatic Diseases
Defects in the lymphatic system can disrupt lymph flow, leading to serious health issues such as breathing difficulties and increased susceptibility to infections. Approximately one in 3,500 infants are born with lymphatic defects, often requiring intensive care. Many individuals with lymphatic anomalies die from sepsis due to impaired immune responses. These defects can lead to ongoing abnormal growth of the lymphatic system, affecting organs and potentially causing organ failure, particularly in the spleen, heart, and lungs.
Lymphatic diseases are frequently misdiagnosed, with correct diagnoses sometimes taking years.
Current genetic diagnosis is severely limited by unidentified genetic causes and restricted access to specialized centers, primarily in large urban hospitals, leaving nearly 80% of patients without a diagnosis.
CLARUM's Innovative Diagnostic Approach
The CLARUM project aims to develop new genetic tests capable of identifying more cases of congenital lymphatic disease, making these tests accessible to medical offices nationwide. Shawber anticipates the CLARUM team will discover 15 or more new genetic mutations linked to lymphatic disease, thereby increasing the predictive value of genetic testing.
Transforming Treatment Options
Identifying genes that cause lymphatic disease can significantly improve treatment options. Currently, 20-30% of patients with lymphatic anomalies caused by specific mutations may benefit from targeted treatments.
Since the initial discovery of lymphatic disease-causing genes about a decade ago, three therapies have been identified, resulting in significant patient improvements, underscoring the need for further gene identification to assist a broader patient population.
Research Methodology and Future Impact
To address the rarity of congenital lymphatic anomalies, CLARUM unites six academic medical centers. These centers will collectively analyze 2,000 patient cases to identify genes. Columbia and CHOP will develop two comprehensive genetic panels for screening specimens obtained through standard clinical care.
The project will also focus on increasing the diagnostic yield of these panels by identifying novel mutations in both known and previously unknown genes. Collaborators from Arkansas Children's Hospital, Boston Children's Hospital, Columbia, and City St. George's University of London will contribute unique cases. The Broad Institute will utilize its genetic bioinformatic pipeline for novel gene identification.
Another crucial aspect of the research involves addressing variants of uncertain significance (VUS), which currently lack sufficient evidence of disease causation.
NYU Langone, City St. George's, and Columbia will develop cell- and zebrafish-based models to rapidly screen VUS for pathogenicity, moving closer to definitive diagnoses.
The Columbia team, in collaboration with the Broad Institute, will develop methods to detect mosaic mutations prenatally. This approach aims to prevent fetuses with cystic lymphatic malformations from receiving potentially ineffective treatments before a genetic diagnosis.
CLARUM plans to develop two genetic tests for clinical use within two years. These tests will use common specimens to detect lymphatic anomalies and screen for germline and mosaic mutations in 73 genes associated with primary lymphatic anomalies. The ultimate goal is to reduce the time for genetic diagnosis from years to weeks, potentially speeding access to FDA-approved therapies.
CHOP and Columbia teams will work with their technology ventures programs to commercialize these genetic panels for nationwide clinical application. Shawber stated that the ARPA-H LIGHT Program support will enable a substantial advancement in genetic testing for lymphatic anomalies.