A team from the Center for Neuroscience and Cell Biology at the University of Coimbra (CNC-UC) and GeneT – Center of Excellence in Gene Therapy developed research that reveals new data for the development of therapeutic approaches for Machado-Joseph disease. This genetic and hereditary neurodegenerative disease primarily affects the Azores, particularly the island of Flores where it affects one in every 140 to 239 adults, and also the central region of the country.
The team used extracellular vesicles, small particles secreted by cells, as a delivery vehicle for the CRISPR-Cas9 system to the brain. This system works as genetic editing "scissors" and was directed to neurons, achieving the inactivation of the mutant ATXN3 gene, which in Machado-Joseph disease is altered by excessive repetitions of CAG chains in the genetic code.
Kevin Leandro, researcher at CNC-UC and first author of the study, explained that the objective was to understand if it would be possible to use extracellular vesicles for a transient exposure to the genetic editing machinery, minimizing unwanted edits. This approach overcomes limitations of conventional viral vectors, ensuring lower immune response, greater encapsulation capacity, and transient expression of the genetic editing tools. The scientists also developed a light-controlled release system using a photocleavable protein.
This is one of the first studies internationally to demonstrate the effectiveness of this approach with extracellular vesicles in the context of Machado-Joseph disease, also known as spinocerebellar ataxia type 3. The disease causes progressive impairment of motor function, speech, swallowing, and fine motor skills, although patients preserve cognitive and intellectual functions.
