A new study led by a team of researchers from the Center for Neuroscience and Cell Biology at the University of Coimbra (CNC-UC) reveals a significant breakthrough in the treatment of Machado-Joseph Disease using extracellular vesicles for gene therapy. Machado-Joseph Disease is a rare hereditary neuropathology that affects people worldwide, particularly in Portugal, specifically the Island of Flores (Azores). Currently, there is no effective therapy available.
 
Machado-Joseph Disease, also known as spinocerebellar ataxia type 3, is a genetic disease caused by a mutation in a specific gene called ATXN3. This mutation leads to the production of a mutated form of the ataxin-3 protein that accumulates in the brain as aggregates, resulting in neuronal dysfunction and death. The disease causes problems with gait, balance, speech, swallowing, eye movements, and sleep. It is an extremely debilitating condition that worsens over time.
 
In order to develop an innovative therapeutic strategy capable of silencing the mutation associated with Machado-Joseph Disease, researchers from the "Gene and Stem Cell Therapy for the Brain" group, led by Luís Pereira de Almeida, President of CNC-UC and lecturer at the Faculty of Pharmacy of the University of Coimbra (FFUC), used extracellular vesicles (biological nanoparticles naturally produced by human cells) as a therapeutic delivery system for silencing agents targeting the brain.
 
«These vesicles act as small 'pouches' capable of carrying genetic material, such as RNA (ribonucleic acid), non-invasively to the intended target, in this case, the neurons, which are one of the most affected cell populations in Machado-Joseph Disease, » explain David Ramos and Kevin Leandro, researchers from CNC-UC and authors of the study.
 
The CNC-UC team employed biotechnological methods to increase the amount of therapeutic material within the extracellular vesicles, specifically artificial microRNAs - small fragments of genetic material with the ability to silence specific genes, preventing their expression. To target the microRNAs to the intended therapeutic target, scientists modified the surface of the extracellular vesicles by introducing a protein called RVG (Rabies Virus Glycoprotein), which specifically directs these particles to neurons.
 
The researchers found that the silencing sequences (microRNAs) incorporated into the extracellular vesicles successfully reached their therapeutic target, effectively silencing the mutant gene associated with Machado-Joseph Disease. This demonstrated a promising therapeutic effect in different cellular and animal models. Additionally, in a mouse model with Machado-Joseph Disease, daily intranasal administration of these vesicles - a non-invasive delivery method - significantly reduced the expression of toxic species of mutant ataxin-3 in the brain of the animals.
 
David Ramos and Kevin Leandro emphasize that «this study contributed to advancements in three distinct scientific domains: the use of extracellular vesicles as delivery vehicles for therapies, the efficacy of RNA interference technology, such as microRNAs, as gene silencing tools, and the development of gene therapies for Machado-Joseph Disease using the intranasal route, a non-invasive method that allows regular administrations of therapy directly to the brain.»
 
This study was published in the scientific journal Molecular Therapy and received funding from the Operational Program for the Center Region 2020 (COMPETE 2020), the Foundation for Science and Technology, the Horizon 2020 program, and the National Ataxia Foundation (USA).
 
 
Carolina Caetano