Monash University is partnering with the University of Missouri and the University of Pennsylvania to develop first-in-class medicines designed to reverse poor lymphatic vessel contraction and transport function, backed by an up to $22.4 million AUD Award from the Advanced Research Projects Agency for Health (ARPA-H).
The researchers join ARPA-H’s GLIDE (Groundbreaking Lymphatic Interventions and Drug Exploration) program to transform how both primary lymphatic diseases and common chronic diseases are treated by developing innovative therapeutics that alleviate, repair or regenerate a dysfunctional lymphatic vascular system.
Professor Arthur Christopoulos, Dean of the Faculty of Pharmacy and Pharmaceutical Sciences, said the work “represents a new frontier” for the field of medicine.
Think of lymphatic vessels as a series of ‘mini pumps’ that drain fluid, waste products and inflammatory cells out of tissues. When these pumps fail, it leads to tissue swelling and inflammation, contributing to lymphedema and chronic diseases like arthritis.
For decades, the standard of care for lymphedema and many lymphatic diseases has been limited, focusing on managing symptoms with lifestyle changes, compression garments or surgeries.
Monash’s research program will work to change that – by developing the first oral medicines specifically designed to restore natural lymphatic pumping and transport function using a highly selective and tuneable molecular mechanism.
The approach, pioneered by the team at Monash Institute of Pharmaceutical Sciences (MIPS), can lead to safer, more selective and more effective medicines acting where and when they are needed, in the right tissue type, while avoiding side-effects in the rest of the body.
The team will use a new model in drug design that has never been applied to lymphatic biology – designing molecules that target “allosteric” binding sites on a specific class of receptor protein found on lymphatic vessels, known as muscarinic acetylcholine receptors.
These unique allosteric drug binding sites act on the target protein similar to a precisely tuned valve or dimmer switch, rather than traditional drugs that activate or block proteins by targeting a simple on-off switch.
The unique features of this allosteric mechanism will allow the medicines to re-set the lymphatic system to healthy levels of functionality, without hitting similar proteins in other parts of the body.
The five-year program is led by MIPS researchers, including Professor Christopoulos, Associate Professor Celine Valant and Professor Natalie Trevaskis.
Professor Christopoulos said: “By mastering the delivery of allosteric drug treatments through the body's lymphatic highways with this level of precision, we can finally target the underlying mechanisms of lymphatic pumping and transport dysfunction in a way that was previously thought impossible.”
Associate Professor Valant said: “Receiving funding from the ARPA-H GLIDE program is an incredible honour and a powerful affirmation of the vision behind our work. We are deeply grateful for the opportunity to partner with ARPA-H to advance solutions for the treatment of lymphedema that have the potential to transform health outcomes for patients around the world.”
Professor Trevaskis said: “For too long, patients living with lymphatic dysfunction have settled for palliative options that don’t address the root cause of their disease – we are working to change that by developing medicines that directly restore lymphatic function.”
The impact of the research extends to treatment of both common and rare conditions including Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, Secondary Lymphedema and Primary Lymphedema, with the potential to treat other lymphatic diseases.
Lymphatic dysfunction is widespread, with Secondary Lymphedema affecting one in 30 adults, while Primary Lymphedema affects one in 100,000. Rheumatoid Arthritis affects one in 50 adults and Juvenile Idiopathic Arthritis affects one in 1,000 children.
The work aligns with the ambitious goals of ARPA-H’s GLIDE program, which aims to develop physical, pharmacologic, gene and cell-based therapeutic interventions to treat primary and rare lymphatic disease and chronic conditions complicated by lymphatic dysfunction. GLIDE is led by ARPA-H Program Manager Dr Kimberley Steele.
The collaboration brings together a multidisciplinary team in MIPS, including the lead investigators together with Professor Peter Scammells (Associate Dean Research and Μedicinal Chemistry Theme), Dr Russel Tait (Director of Enterprise and Engagement), Associate Professor David Thal (Drug Discovery Biology), Associate Professor David Shackleford (Centre for Drug Candidate Optimisation) and Dr Mohammad Abdallah (Drug Delivery, Dynamics and Disposition).
The broader collaborative network involved in this research program include Professor Flavia Cicuttini, (Monash University and Head of Rheumatology, Alfred Hospital), Dr Michael de Veer (Monash Biomedical Imaging), Professor Mike Davis and Dr Scott Zawieja (Uni. Missouri), Professor Max Itkin and Associate Professor Jasmine Zheng (Uni. Pennsylvania) and lived experience ambassador, Ms Susan Haywood.
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