Researchers from the University of Coimbra develop promising therapeutics for the treatment of Machado-Joseph Disease

English version: Diana Taborda

A novel study led by a research team of the Centre for Neuroscience and Cell Biology of the University of Coimbra (CNC-UC) shows a significant breakthrough in the treatment of Machado-Joseph disease, based on the use of extracellular vesicles for genetic therapeutics. Machado-Joseph disease is a rare hereditary neuropathology that affects people all over the world, especially in Portugal, in the Azores islands. To date, there is no effective therapy available.

Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is a genetic disorder caused by an abnormality in a gene called ATXN3. SCA3 is characterized by the accumulation of abnormal ataxin-3 protein aggregates in various regions of the brain, leading to neuronal dysfunction and ultimately cell death. The disease causes difficulties in walking, balance, speech, swallowing, eye movements and sleep. It is an extremely debilitating condition that gets worse over time.

With the purpose of developing a novel therapeutic strategy capable of silencing the mutation associated with Machado-Joseph disease, researchers from the group "Gene and Stem Cell Therapies for the Brain", coordinated by Luís Pereira de Almeida - president of CNC-UC and professor at the Faculty of Pharmacy, University of Coimbra (FFUC) - used extracellular vesicles (biological nanoparticles, produced naturally by human cells) as delivery vehicles of silencing sequences to the brain.

The authors of the study, David Ramos and Kevin Leandro explain that “these vesicles act as small 'pouches' able to carry genetic material such as RNA in a non-invasive way to the intended target, in this case to neurons, which are one of the brain cell populations most affected by Machado-Joseph disease”.

The CNC-UC team used biotechnology-based methods to increase the amount of therapeutic material carried by the extracellular vesicles (EVs), more specifically artificial microRNAs - small fragments of genetic material with the ability to silence specific genes, thus blocking their expression. In order to guide the microRNAs to the therapeutic target, the scientists modified the surface of EVs by inserting rabies virus glycoprotein (RVG) peptides, which specifically direct these particles to the neurons.

The researchers found that the silencing sequences (microRNAs) incorporated into EVs reached their therapeutic target, effectively silencing the mutant gene associated with Machado-Joseph disease, thus showing promising therapeutic results both in different cellular models and in animal models. In addition, the team discovered that non-invasive daily intranasal administration of these vesicles in a mouse model with MJD significantly reduced the expression of the toxic properties of mutant ataxin-3 species in the model's brain.

David Ramos and Kevin Leandro note that “this study has contributed to advances in three distinct scientific domains: the use of extracellular vesicles as therapeutic delivery vehicles; the effectiveness of RNA interference technology - such as microRNAs - as a gene silencing tool; and the development of genetic therapeutics for Machado-Joseph disease using the intranasal route, a non-invasive method that allows regular therapeutic administrations directly into the brain”.

The study was published in the journal Molecular Therapy and was funded by the COMPETE 2020 Programme, the Portuguese Foundation for Science and Technology, the Horizon 2020 Programme and the National Ataxia Foundation (USA).