2024/12/12

Researchers discover postal code that allows proteins to hitch a ride around the body

Researchers have identified an 18-amino acid code that enables proteins to adhere to exosomes, facilitating the development of targeted therapies for diseases such as Duchenne muscular dystrophy.

This breakthrough, published in Science Advances, overcomes a key challenge in the therapeutic use of Wnt7a, a drug for muscle regeneration, by improving its distribution in the body.

Exosomes, now used to transport therapeutic proteins, open new possibilities in muscle regeneration and the treatment of neurodegenerative and oncological diseases.

An international research team, including Dr. Uxía Gurriarán-Rodríguez, first author and current researcher at CIC bioGUNE, has identified an 18-amino acid code that enables Wnt proteins to attach to exosomes, paving the way for a new generation of targeted therapies. The study, published in Science Advances, has significant implications for the development of innovative treatments for diseases like Duchenne muscular dystrophy.

The study, primarily conducted during Dr. Gurriarán-Rodríguez's time at the Ottawa Hospital and the University of Ottawa (Canada), details the discovery of the Exosome Binding Peptide (EBP), a region of the Wnt7a peptide responsible for its binding to exosomes. This breakthrough addresses one of the major challenges in using Wnt7a as a therapeutic agent: its limited biodistribution due to its lipophilic nature.

"For years, researchers have tried to turn Wnt7a into a drug for muscle regeneration, but it is very difficult to distribute Wnt7a throughout the body because it is covered in fat molecules that don't mix well with body fluids," explained Dr. Uxía Gurriarán-Rodríguez, lead author of the study and former postdoctoral researcher in Dr. Michael Rudnicki's group. "Now that we know how Wnt7a binds to exosomes, we have solved this problem and can accelerate the development of drugs for devastating diseases like Duchenne muscular dystrophy."

This study exemplifies the power of international and multidisciplinary collaboration. It features valuable contributions from scientists at CIC bioGUNE, member of BRTA, whose expertise in advanced crystallography and mass spectrometry tools was crucial to the study. CIC bioGUNE’s advanced proteomics capabilities complemented the computational and experimental work carried out in Ottawa and at the Centro de Regulación Genómica (CRG) in Barcelona.

A new frontier in exosome-based therapies
Exosomes, tiny extracellular vesicles, have gained attention in biotechnology for their ability to carry therapeutic molecules. With the discovery of EBP, the team demonstrated that it is possible to "tag" specific proteins for transport by exosomes, thus enhancing their delivery within the body.

This approach holds tremendous potential across multiple fields, from muscle regeneration to the treatment of oncological and neurodegenerative diseases. "Proteins are the body's natural medicines, but they don't always distribute well throughout the body," said Dr. Michael Rudnicki, lead author of the study, director of the Regenerative Medicine Program at the Ottawa Hospital, and Professor at the University of Ottawa. "This discovery allows us to use exosomes to distribute any protein throughout the body, opening the door to a completely new field in drug development."

This research was funded by Defeat Duchenne Canada, the Canadian Institutes of Health Research, the U.S. National Institutes of Health, the Frederick Banting and Charles Best Canada Graduate Scholarships Program, the Ontario Institute for Regenerative Medicine, the Stem Cell Network, and the Spanish Ministry of Science and Innovation.

Reference: Uxía Gurriarán-Rodríguez, David Datzkiw, Leandro G. Radusky, Marie Esper, Ehsan Javandoost, Fan Xiao, Hong Ming, Solomon Fisher, Alberto Marina, Yves De Repentigny, Rashmi Kothary, Mikel Azkargorta, Felix Elortza, Adriana L. Rojas, Luis Serrano, Aitor Hierro, and Michael A. Rudnicki. Identification of the Wnt signal peptide that directs secretion on extracellular vesicles. Science Advances. DOI: 10.1126/sciadv.ado5914.

About the Ottawa Hospital
The Ottawa Hospital (TOH) is one of Canada’s leading teaching and research hospitals, guided by its vision of providing world-class, compassionate care that everyone would want for their loved ones. This multi-campus hospital, affiliated with the University of Ottawa, is home to the Regional Trauma Center and the Cancer Center, and discovers advances adopted globally. Supported by generous community contributions, it focuses on transforming the future of healthcare to improve the health of a diverse patient population from Eastern Ontario, Western Quebec, and Nunavut.

About the University of Ottawa
The University of Ottawa is home to more than 50,000 students, faculty, and staff who live, work, and study in both French and English. Its campus is a crossroads of cultures and ideas, where bold minds come together to inspire transformative ideas. Ranked among the top 10 research universities in Canada and in the top 200 worldwide, it attracts exceptional thinkers and welcomes diverse perspectives from around the globe.

About CIC bioGUNE
The Centre for Cooperative Research in Biosciences (CIC bioGUNE), member of the Basque Research & Technology Alliance (BRTA), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies.

About BRTA
BRTA is an alliance of 4 collaborative research centres (CIC bioGUNE, CIC nanoGUNE, CIC biomaGUNE y CIC energiGUNE) and 13 technology centres (Azterlan, Azti, Ceit, Cidetec, Gaiker, Ideko, Ikerlan, Leartiker, Lortek, Neiker, Tecnalia, Tekniker y Vicomtech) with the main objective of developing advanced technological solutions for the Basque corporate fabric.

With the support of the Basque Government, the SPRI Group and the Provincial Councils of the three territories, the alliance seeks to promote collaboration between the research centres, strengthen the conditions to generate and transfer knowledge to companies, contributing to their competitiveness and outspreading the Basque scientific-technological capacity abroad.

BRTA has a workforce of 3,500 professionals, executes 22% of the Basque Country's R&D investment, registers an annual turnover of more than 300 million euros and generates 100 European and international patents per year.

Spanish version