Lymphatic Anomalies Registry
Principal Investigator: Cameron C. Trenor III, MD
Institution: Children’s Hospital Boston
The Vascular Anomalies Center (VAC) at Boston Children’s Hospital is developing a Lymphatic Anomalies Registry. Leadership for this project includes the VAC co-director Dr. Steven Fishman, Dr. Denise Adams, HVMC Director at Cincinnati Children’s Hospital Medical Center and principal investigator Dr. Cameron Trenor, Director of Clinical Research at the VAC. Initial work will retrospectively compile available data and, with patient consent, collect missing data by contacting patients, families and referring physicians to better understand the natural history of these diseases, response to therapies and long-term outcomes. A prospective registry will also be established to collect data going forward. The major goal of this project is to improve knowledge about these diseases toward the design of future clinical trials for lymphatic diseases. Eligible diagnoses include lymphatic malformations, Gorham disease, generalized lymphatic anomaly (including “lymphangiomatosis”), Kaposiform lymphangiomatosis, Kaposiform hemangioendothelioma, Klippel-Trenaunay (capillary/lymphatic/venous malformation), CLOVES and other complex vascular lesions, syndromes with abnormal lymphatics and lymphatic tumors. The VAC at Boston Children’s Hospital will be contacting patients known to them and interested patients can contact the VAC for information on participation at 617-355-5226.
Transgenic mouse model to determine the mechanism and treatment of congenital pulmonary lymphangiectasia and lymphangiomatosis
Investigator: Donald M. McDonald, MD, PhD
Institution: University of California, San Francisco
In this project the McDonald lab is using a new genetically engineered mouse model to determine the mechanism and identify potential treatments for pulmonary lymphangiectasia and lymphangiomatosis, where abnormally dilated, dysfunctional lymphatic vessels grow in the airways and lung. Children with this condition have severe respiratory distress and impaired lung function. There is no specific treatment. To address the problem, Dr. McDonald’s group developed the CCSP-VEGF-C mouse model, in which VEGF-C is overexpressed in the respiratory epithelium under doxycycline regulation. Through support of the LMI, they are using the model to examine the mechanisms underlying the development and reversal of lymphangiectasia. They recently obtained evidence that treatment with the mTOR inhibitor rapamycin can convert lymphangiectasia into more normal lymphatics. His group found that in the absence of therapy, lymphangiectasia persisted indefinitely, with little or no spontaneous remission. Inhibition of VEGF-C receptor signaling prevented but did not reverse the condition. However, treatment with rapamycin significantly reversed the lymphatic abnormality. By comparison, treatment with the corticosteroid dexamethasone, beta-adrenergic receptor antagonist propranolol, gamma secretase inhibitor DAPT, or autophagy inhibitor chloroquine had less or no benefit and in some cases made the condition worse. Their research is now examining the mechanisms by which rapamycin reverses lymphangiectasia. They are also determining whether the efficacy can be increased by blocking other components of signaling pathways involving lymphatic growth factor receptors, PI3-kinase, Akt, and mTOR. The long-term goal is to find efficacious strategies for reversing lymphangiectasia and other lymphatic malformations and to understand the mechanisms of the action.
Genetic and genomic analysis in patients affected by Gorham-Stout Disease and General Lymphatic Anomalies
Institution: Institute of Medical and Molecular Genetics (INGEMM), Madrid, Spain
The Birthmark & Vascular Anomalies Center at La Paz Children´s Hospital —founded by Dr. Lopez Gutierrez in 1995 as the referral tertiary institution in Spain for the multidisciplinary care of Vascular Anomalies— and the Institute of Medical and Molecular Genetics (INGEMM) —founded by Dr. Lapunzina in 2008 with the vision of improving health care for patients with rare genetic diseases— have been studying the last 5 years the genetic causes of lymphatic and vascular malformations. In the past year Dr. Martinez-Glez —Clinician and researcher with a special interest in vascular/lymphatic malformations and/or overgrowth syndromes— has joined the team as responsible of combine efforts within the project, and in collaboration with L. Rodriguez-Laguna, MSc, is performing molecular studies in patients with Gorham Disease (GD) and Generalized Lymphatic Anomaly (GLA). The current objectives include the registration of patients in a specific database of GD/GLA, the study of patients/samples with osteolysis and GLA using whole genome SNP-array and NGS studies (exome and panels), and the development of a bioinformatic algorithm for the systematic analysis of both array and NGS data.
Bone cells and lymphatic endothelium interface
Institution: University of Rochester
Gorham-Stout syndrome (GSS) is a rare disease, which is characterized by bone loss and abnormal formation of vascular channels and fibrous tissue. Its etiology and the cell types involved are completely unknown and there is no effective therapy. Several theories have been proposed postulating that super-active osteoclasts (OC) resorb bone and anti-resorptive medicine has been used clinically to treat patients with GSS. However, the OC theory is challenged by some clinical reports in which OCs are not identified in the tissue sections from GSS patients. In addition, because bone mass is maintained by a balance of OC-mediated bone resorption and osteoblast (OB)-mediated bone formation, if OB function is impaired in GSS has not been studied. One of pathologic features of GSS is the presence of a large amount of lymphatic vessel-like structures within the bone marrow (BM) cavity, raising the speculation that there may be a cross-talk between bone cells, including OCs and OBs, with lymphatic endothelial cells (LECs) at the BM. Recently, the Xing lab reported that significantly increased LEC precursors in mouse models of inflammatory-erosive arthritis and some of these cells also express surface marker for macrophage/OC precursors. OCs produce high levels of VEGF-C and LECs express M-CSF, a cytokine that stimulates OCs and inhibits OBs. Thus, they hypothesize that LECs and OCs are derived from common precursors from the BM and bone cells interact with LECs. In this project, they plan to use BM-derived OCs, OBs, and LECs to investigate if OCs and LECs share a common precursor, if OCs affect LEC function, and if LECs regulates OB differentiation. Results will provide critical information regarding interaction between bone cells and LECs, which will help better understand the cell type involvement of GSS pathology.
Identification of biomarkers for patients with Generalized Lymphatic Anomaly (GLA), Kaposiform Lymphangiomatosis (KLA), Gorham-Stout Disease (GSD
Institutions: Cincinnati Children’s Hospital Medical Center,
Boston Children’s Hospital
While lymphatic anomalies are rare diseases, they can be life-threatening and devastating to affected children and their families. Advances in diagnosis, monitoring and therapies will be significantly improved if non-invasive biomarkers that are sensitive and specific can be identified. Biomarkers may also give insights into disease pathogenesis and can lead to new therapeutic targets as they are often released by cells that contribute to the disease process. The goal of this project is to identify and characterize blood biomarkers to aid in the diagnosis of patients with lymphatic anomalies. The diagnosis of patients with lymphatic anomalies can be challenging and obtaining a tissue biopsy can worsen the disease and so identification of specific blood biomarkers is highly desirable. This study will measure angiogenic factors, including VEGFs (A, C, D) and Angiopoeitins-1 and -2 in serum and plasma samples. Patients included in the study are those with: 1) generalized lymphatic anomaly (GLA); 2) kaposiform lymphangiomatosis (KLA); 3) Gorham Stout disease syndrome (GSD) and 4) kaposiform hemangioendothelioma (KHE) which also has a lymphatic component. Blood samples will be analyzed at baseline and also in patients that receive rapamycin therapy. The multidisciplinary team of investigators at Cincinnati Children’s Hospital, a major center for vascular anomalies, have extensive expertise, are highly collaborative and have strong preliminary data that supports the studies.
Development of an animal model of Gorham-Stout disease
Institution: UT Southwestern Medical Center
Gorham-Stout disease (GSD) is a rare disorder characterized by the proliferation of lymphatic vessels in bone and by the replacement of bone with fibrous tissue. Unfortunately, our understanding of GSD has not advanced significantly since Gorham and Stout published the clinical and histological features of this disease in 1955. It remains unclear as to what is driving bone loss in GSD and effective therapies for this devastating disease have not been identified. The study of GSD has been hindered, in part, by the lack of an animal model of the disease. The Dellinger Lab is attempting to fill this need and is testing the hypothesis that mice genetically engineered to overexpress vascular endothelial growth factor-C (VEGF-C) in their bones will display characteristics similar to patients with GSD. These mice could be used to improve our understanding of the mechanisms driving bone loss in GSD and to help identify therapies for GSD.
2015 MDBR Funds 3 Studies
Lymphatic Imaging and Intervention Center at The Children’s Hospital of Philadelphia
University of Pennsylvania
Project: Dynamic Contrast Enhanced MR Lymphangiogram Imaging of Lymphatic Anomalies
The Lymphatic Imaging and Intervention Center at The Children’s Hospital of Philadelphia, received a $101,000 grant for the purpose of imaging the lymphatic system. Specifically, the study aims to demonstrate thoracic lymphatic anatomy in patients with lymphangiomatosis/Generalized Lymphatic Anomaly (GLA), Gorham-Stout disease (GSD), or Kaposiform Lyphangiomatosis (KLA) using heavy weighted T2 MR and Dynamic Contrast-Enhanced MR Lymphangiogram (DCMRL) to better understand lymphatic anatomy and lymph fluid flow in patients with Lymphatic Anomalies.
The major cause of mortality and morbidity in these patients is the deterioration of pulmonary function by chronic chylous effusions and progressive interstitial lung disease. The understanding of changes in patients’ pulmonary lymphatic anatomy is hindered by the difficulty of imaging of the lymphatic system.
DCMRL is a technique that has recently been developed, allowing dynamic MR imaging of the lymphatic system by injecting gadolinium contrast agent into the lymph nodes in the patient’s groin to perform imaging instead of gaining access from the foot, as in traditional lymphangiogram. Focusing on imaging of the deep lymphatic vessels in chests of patients with these rare lymphatic malformations and pulmonary involvement of the disease will enable the team to gain understanding of how these deranged lymphatics behave in the chest and their impact on pulmonary function.
Co-directors of the Center are Dr. Maxim Itkin and Dr. Yoav Dori who have dedicated their careers to the development of advanced, non-invasive methods to image the lymphatic system. Dr. Itkin is the principal investigator on this project. Study participants will be recruited through the International LGDA Registry for Lymphatic Malformations.
David Cormode, PhD
University of Pennsylvania
Project: Nano-magnetic Oils for the Study of Intestinal Lymphatics in Lymphangiomatosis
Lymphangiomatosis/Generalized Lymphatic Anomaly (GLA) is a condition where abnormally proliferating lymphatic vessels cause disruption to organs such as the intestines, liver, lungs and bone. The lymphatic vessels coming from the intestine are a key part of the lymphatic system and are frequently involved in lymphangiomatosis/GLA. One of the main issues with understanding, diagnosing and treating lymphangiomatosis/GLA is the lack of methods to visualize lymphatic vessels; and of all lymphatic systems, the intestinal lymphatics particularly lack imaging approaches.
This study seeks to develop a new contrast agent using iron oxide-labeled oils that will be administered orally so iron oxides can be taken up and distributed into the intestinal lymphatic vessels via chylomicrons, thereby allowing for the visualization of intestinal lymphatics using magnetic resonance imaging (MRI). The contrast agent will be fed to healthy mice and to mice that have lymphangiomatosis. The mice will undergo MRI to measure the effectiveness of the contrast in visualizing the intestinal lymphatic vessels. Successful uptake of the nano-magnetic oils into the intestinal lymphatics will allow for the visualization of these vessels that is necessary to facilitate the development of treatments and enhance our understanding of the disease.
Dr. Cormode’s research focuses on the development of novel and multifunctional nanoparticle contrast agents for medical imaging applications.
Joseph Rutkowski, PhD
Texas A&M Health Science Center School of Medicine
Project: Inducible Lymphatic Hyperplasia to Drive Chylous Accumulation Mimicking Lymphangiomatosis
The process of lymphatic endothelial cell hyperproliferation (an abnormally high rate of cell division) results in the increase in both the size and number of lymphatic vessels observed in lymphangiomatosis/Generalized Lymphatic Anomaly (GLA). VEGF-D is a type of protein that is a powerful driver of lymphatic proliferation. Dr. Rutkowski’s lab has developed a novel mouse line in which it has induced the over-expression of VEGF-D, producing massive and deranged lymphatic expansion in the mice resulting in chyloascites and the eventual, lethal chylothorax mimicking lymphangiomatosis/GLA.
One advantage of this drug-inducible transgenic system is that it is dose-dependent. Dr. Rutkowski’s lab will be further characterizing this dose dependence, seeking to identify early peripheral manifestations, such as increased tissue fluid accumulation that might precede chylothorax. The lab will also seek to identify the dietary fatty acids and changes in lymph composition that specifically amplify VEGF-D signaling effects.
With the ability to tightly control lymphatic proliferation, Dr. Rutkowski’s lab proposes that the results of this study will provide a novel platform to study the manifestation and therapeutic maintenance of lymphangiomatosis.
Since the beginning of his PhD studies, Dr. Rutkowski’s research has focused on lymphatic vessel biology, lymphangiogenesis, and the physiology of lymphatic diseases. His recent work has focused on developing new genetic mouse models that permit specific manipulations of lymphatic endothelial cell biology. The funded project will support an exciting and potentially clinically-relevant new model that may provide a novel platform on which to test the manifestation of lymphangiomatosis/GLA, disease progression, and potential remediation.