TheraLymph program: Gene Therapy to restore lymphatic flow lymphedema
The main objective of the TheraLymph project is to develop a treatment for Lymphedema using multi-gene delivery LentiFlash® technology in a non-integrative gene therapy approach. The project consortium's translational research program brings together scientists and physicians from 5 European countries and is focused on patients who developed Lymphedema after breast cancer surgery. The project goal is to validate the best molecule combination for gene therapy and to finalize phase I/II clinical trials at the affiliated hospital.
For more information, please visit the Theralymph+ project website.
Timeline & Funding
The Theralymph project was launched in 2020 for the duration of 5 years and has received funding from the EU Horizon 2020 research and innovation program under Grant Agreement No 874708.
Objectives & Technical challenges
Lymphedema is a lymphatic vascular system disorder characterized by impaired lymphatic return and swelling of the extremities. Accumulation of undrained fluid/lymph results in fibrosis and adipose tissue deposition in the affected arm or leg. It can be inherited or occurs after cancer surgery and lymph node removal. Indeed, 10-15% of women develop lymphedema after surviving breast cancer. It is a common disease affecting more than 120 million people worldwide and causing a significant morbidity, however there is no curative treatment for lymphedema.
Three main tasks constitute the project:
- In vitro validation of therapeutic targets identified by the different partners, such as VEGFC and another factors to restore the lymphatic collecting network
- In vivo determination of the efficacy of LentiFlash® particles as an RNA delivery compared to an integrative lentivector, in lymphedema mouse models
- Treating patients using multi-gene delivery LentiFlash® technology.
University of Helsinki
This project will be carried out in the Biomedicum Helsinki Research Center, which is a unique environment, one of few in Europe where all fields of biomedical research are located in the Academic Medical Center Helsinki (AMCH). The Translational Cancer Biology group, led by Dr. Alitalo, investigates the induction of lymphatic vessel growth and its benefits in lymphedema, using viral vector transduction, as well as the organ-specific heterogeneity and functions of lymphatic vessels using a combination of state-of-the-art molecular, cellular and genetic in vivo methods. The group also investigates the role of meningeal lymphatic vasculature in neuroinflammation and neurodegenerative diseases. The team further characterizes responses of lymphatic vessels to cancer therapies, with a focus on clinically relevant immunotherapy approaches.
University of Lausanne
Vascular and Tumor Biology Laboratory is part of the Department of Oncology of UNIL and is an adjunct member of Lausanne branch of Ludwig Institute for Cancer Research Lausanne, that is specializing in tumor immunology and immune therapy. Their main research interests are in the molecular mechanisms of lymphatic and blood vessel growth and remodeling, and their role in normal organ function and diseases, such as inflammation and cancer.
University of Uppsala
The Vascular Development Laboratory headed by Dr. Mäkinen develops and utilizes genetic mouse models in combination with molecular and cell biological approaches to study mechanisms that regulate the morphogenesis and functional specialization of the vasculature. The lab also investigates how regulators of developmental (lymph)angiogenesis impact on genetic human diseases such as lymphoedema and vascular malformations.
University of Liège
The Laboratory of Biology of Tumor and Development (LBTD) belongs to the GIGA-Cancer in the GIGA Research Center (ULg), a major multidisciplinary center of research in life sciences composed of >600 researchers. In this center, team members have access to fully equipped and staffed core facilities and platforms. One of the main topics of research include cancer and tumor microenvironment, with a particular interest on angiogenesis and lymphangiogenesis in the context of breast cancer.
De Duve Institute
The Laboratory of Human Molecular Genetics, headed by Prof Miikka Vikkula, MD, PhD, focuses on characterization of the underlying pathophysiology of vascular anomalies, such as lymphedema, as well as cleft lip and palate, and selected cancers. The long-term goal is to develop molecular precision therapies for these disorders. The lab is specialized in evaluating the contribution of genetic variation to human disease. This research is based on blood and tissue samples collected from patients in collaboration with clinicians and multidisciplinary centers worldwide.
The lab analyses patients’ genomes using highthroughput (NGS) sequencing, including targeted panels, WES (whole exome sequencing), WGS (whole genome sequencing) and RNAseq. With its full-time bioinformatician, the group has developed an in-house software called Highlander implementing specialized bioinformatic tools for NGS analyses.
The Laboratory of Pathophysiology of Adipose Tissue presented a number of important contributions in studies focused at changes of metabolic, endocrine and immune characteristics of AT during lifestyle - diet and physical activity- interventions in obese population. The main aim of the present activity is to elucidate a role of lipogenic and adipogenic capacity and inflammatory state of AT in ethiopathogenesis of obesity, type 2 diabetes, lymphedema and in pathogenesis of metabolic disturbances associated with aging. Laboratory is focused on clinical and translational research combining clinical studies with patients and in vitro laboratory techniques to analyze processes that underlie, or mediate disturbances related to dysfunctional adipose tissue.
The PI laboratory is located in the Institute of Cardiovascular and Metabolic Diseases (I2MC) created in 2011 by Inserm. The research activity focuses on metabolic, cardiovascular and renal diseases. The main feature of I2MC is the gathering of basic scientists together with clinicians working on metabolic risk factors (obesity, diabetes and dyslipidemia) and their cardiovascular complications (thrombosis, atherosclerosis, cardiac and renal failure).
The laboratory headed by Dr Garmy-Susini studies molecular regulations of (lymph)angiogenic factors in vascular pathologies. It developed research axes in the field of gene expression control in response to stress and in pathophysiology of the lymphatic system, connected to therapeutic axes of gene therapy of ischemic heart disease and lymphedema. The main objectives of the lab are to 1/identify the pathophysiology of the lymphatic system in lymphedema, 2/characterize regulation of lymphangiogenesis-related gene expression in stress conditions (hypoxia, ER stress…), and 3/develop innovative therapies to restore lymphatic flow to improve healing in ischemic heart and in lymphedema.
The project is held by the Institute for Research on Cancer and aging of Nice (IRCAN). The team of Gilles Pagès focuses its research on the regulation of angiogenic factors and their role as markers of sensitivity or resistance to different cancers treatments. The first major paper of the team described the efficacy of Gleevec in chronic myeloid leukemia; (Legros, L et al Blood, 2004). More recently the team focused on renal cell carcinoma and published pivotal papers on the mechanisms of resistance to anti-angiogenic drugs.