Therapeutic effects of engineered exosome-based miR-25 and miR-181a treatment in spinocerebellar ataxia type 3 mice by silencing ATXN3

BackgroundSpinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant hereditary ataxia worldwide, which is however in a lack of effective treatment. In view of that engineered exosomes are a promising non-invasive gene therapy transporter that can overcome the traditional problem of poor drug delivery, the aim of this study was to evaluate, for the first time, the value of exosome-based microRNA therapy in SCA3 and the therapeutic effects of intravenously administrated ATXN3 targeting microRNAs in transgenic SCA3 mouse models.MethodsThe rabies virus glycoprotein (RVG) peptide-modified exosomes loaded with miR-25 or miR-181a were peripherally injected to enable targeted delivery of miRNAs to the brain of SCA3 mice. The behaviors, ATXN3 level, purkinje cell and other neuronal loss, and neuroinflammation were evaluated 4 weeks after initial treatment.ResultsThe targeted and efficient delivery of miR-25 and miR-181a by modified exosomes substantially inhibited the mutant ATXN3 expression, reduced neuron apoptosis and induced motor improvements in SCA3 mouse models without increasing the neuroinflammatory response.ConclusionsOur study confirmed the therapeutic potential of engineered exosome-based miR-25 and miR-181a treatment in substantially reducing ATXN3 aggregation and cytotoxicity by relying on its targeted and efficient drug delivery performance in SCA3 mice. This treatment method shows a promising prospect for future clinical applications in SCA3.