Deciphering the role of ephrin B2 mutation in the pathogenesis of central conducting lymphatic anomaly

Awardee: Shoshana Greenberger

Institution: Newcastle University

Grant Amount: $62,398

Funding Period: February 1, 2025 - January 31, 2026

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Summary:

Summary of the project: Recently, we have identified a novel mutation in a gene Ephrin-B2 (EFNB2) that causes a change in amino acid sequence of the protein, resulting in a severe lymphatic anomaly (CCLA) in a child patient. This child shows several severe symptoms, all linked to the function of the lymphatic system. We assume that the mutation in EFNB2 causes the disease by the disruption of the structure and function of lymphatic vessels through the erratic activity of the important signal transduction pathways. We were able to isolate the lymphatic endothelial cells (LEC) from this patient. Thus we have a unique opportunity to study the effect of this mutation on both structure and function of the lymphatic vessels. Herein we propose to study a novel genetic cause of this central conducting lymphatic anomaly by: (1) characterizing the effect of EFNB2 mutation on the cellular function and signaling in patient-derived lymphatic cells, and (2) creating a zebrafish model, with mutant EFNB2 in order to decipher the effect of the mutation on lymphatic system development, creating a tool that could be used in future drug screening. We believe that this study will expand our knowledge of the role of EFNB2 in the lymphatic disease, towards our better understanding of the underlying pathogenic processes, bringing about the possibility to find a remedy for the disease.

CLA Chatbot: Developing a Scalable Artificial Intelligence-Powered Communication Tool for Families Affected by Complex Lymphatic Anomalies

Awardee: Bryan Sisk

Institution: Washington University

Grant Amount: $60,679.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Complex lymphatic anomalies (CLAs) affect the development, structure, and function of the lymphatic system causing variable and often severe clinical manifestations that are difficult to diagnose and treat. Accessing high-quality information is essential to receiving optimal care for patients with CLAs. In prior study of patients and caregivers with CLAs or other vascular anomalies, we found that having better quality of information exchange with clinicians was associated with better physical health, mental health, and ability to navigate the healthcare system. Parents also viewed accessing high-quality information as central to their role as advocates. Yet, most families with CLAs report poor communication with clinicians, limited access to reliable information, and reliance on social media and internet searches for information. To improve understanding and support the ability of patients and caregivers to manage CLAs, we will develop a novel and scalable communication tool that retrains ChatGPT large language model (LLM) to answer questions about complex lymphatic anomalies (CLAs). We hypothesize that CLA Chatbot will provide accurate, understandable, and comprehensive responses to questions generated by patients with CLAs and caregivers. CLA Chatbot will be scalable, easily translatable to other rare diseases, and will directly inform future federally funded efficacy trials.

A novel Zebrafish model of Kaposiform Lymphangiomatosis: A tool for drug discovery

Awardee: Karina Yaniv

Institution: Sheba Medical Center

Grant Amount: $68,650.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Kaposiform lymphangiomatosis (KLA) is a member of a broad family of complex lymphatic anomalies (CLA)- rare disorders characterized by the abnormal proliferation of lymphatic vessels in the skin and internal organs. KLA, the most aggressive and rarest form of these disorders, can occur at any age, but the incidence is highest in children and teenagers. Current pharmaceutical treatments are aimed chiefly at managing the symptoms; thus, the 5-year survival rate for children affected by KLA is only about 50%. Therefore, there is an urgent need for new pre-clinical models recapitulating the disease and enabling the identification of novel drug targets. This study aims to characterize a novel KLA zebrafish model we recently established in our lab and to screen for new avenues of treatment. Because of their small size, transparency, and large progeny, ZF have become an attractive means for assessing compound effects at early stages of drug discovery. Recently, a lifesaving treatment for a lymphatic anomaly was identified through a chemical screen based on our early establishment of the ZF as a superb model for the study of lymphatic biology. Here we will harness the power of our novel mutants to screen for compounds that selectively revert the KLA-related phenotypes. We anticipate that completion of this study will help increase our understanding of the etiology of KLA and will lead to the identification of new efficient therapies.

Molecular mechanisms of EPHB4 pathogenesis – towards new treatment development for lymphatic anomalies

Awardee: Silvia Martin Almedina

Institution: St. George’s University of London

Awarded: $25,000

Funding Period: September 1, 2022 - August 31, 2023

Analysis of a new therapeutic approach to inhibit osteolysis in Gorham-Stout Disease

Awardee: Michela Rossi, PhD

Institution: Bone Physiopathology Research Unite, Bambino Gesu Children’s Hospital, Rome

Awarded: $25,000

Funding Period: September 1, 2022 - August 31, 2023

Identifying Unmet Care and Communication Needs of Families Affected by Complex Lymphatic Anomalies

Awardee: Bryan Sisk

Institution: Washington University School of Medicine

Grant Amount: $53,460

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Complex lymphatic anomalies (CLAs) are a group of rare disorders associated with abnormal lymphatic development that arise in infants and children. These disorders can be disfiguring, painful, and even life-threatening. In our clinical experiences, families affected by CLAs have described multiple barriers to care and communication, such as difficulty accessing care from CLA experts, persistent uncertainty about the diagnosis and long-term consequences, insufficient information to guide decisions, and the necessity of persistent parental advocacy to ensure the child receives adequate medical care. However, no researchers have explored or categorized the needs or barriers experienced by these families. Without this critical information, we cannot provide guidance to clinicians, patients, parents, or advocacy groups on how to best support these families to overcome care and communication challenges. Furthermore, this foundational knowledge is necessary to support the development of interventions and systemic changes to improve care for these families. In this study, we will characterize the care and communication needs of families affected by CLAs and identify resources and coping strategies from the perspectives of parents using qualitative semi-structured interviews (Aim 1). We will also assess the psychosocial wellbeing of parents and the quality of communication using survey methodology (Aim 2). To disseminate findings and seek feedback from the CLA community (Aim 3), we will host separate interactive webinars with the Lymphangiomatosis and Gorham’s Disease Alliance (LGDA) and the Chan-Zuckerberg Institute (CZI) Lymphatic Researchers Network. These findings will be essential to improve care and ensure that scientific discoveries translate to actual clinical benefits for families affected by CLAs.