Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) is the most prevalent autosomal dominantly-inherited spinocerebellar ataxia in the world. Neurodegeneration in MJD occurs in selective brain regions resulting in a wide spectrum of clinical symptoms such as postural instability, ataxia and oculomotor impairments. Clinical manifestations are severe in MJD patients leading to premature death. Unfortunately, there is still no treatment available. Transcriptional dysregulation and particularly dysregulation of microRNAs (miRNAs), which are small molecules of non-coding RNAs that negatively regulate mRNAs expression, has been shown to play a role in MJD pathogenesis. However knowledge on this subject and in the possibility of using miRNAs as a therapeutic strategy is still very scarce. In a previous work, we demonstrated that delivery of let-7 miRNA to the striatum of a lentiviral (LV) mouse model of MJD was sufficient to reduce neuronal protein aggregation in the context of significantly upregulated LC3-II levels, thus indicating that let-7-mediated autophagy activation is beneficial to MJD. In addition, very recently our group identified mir-9, mir-181a and mir-494 predicted to target ATXN3 3’UTR. Overexpression of these miRNAs, which are abnormally downregulated in MJD models, effectively reduced mutATXN3 levels and ameliorated the associated MJD neuropathology. These achievements demonstrate that it is of crucial importance to pursue with the investigation of miRNA pathway involvement in MJD. Although miRNA-based drugs have still not be approved by FDA for medical intervention, some candidates are currently in phases 1/2 of clinical trials or in clinical development. However, there are some FDA-approved drugs capable of modulating miRNA levels (miRNA small molecule modifiers). Enoxacin, being fluoro-quinolone derivative, belongs to a family of approved antibiotic drugs and was shown to induce a general upregulation of miRNA population. In the contrary, aminoglycoside antibiotics, such as Kanamycin and Streptomycin, have been previously described as inhibitors of Dicer-mediated precursor miRNA (pre-miRNA) processing. Although these molecules have enormous potential, they constitute general activators or inhibitors of miRNAs and a specific miRNA selectively is not possible. However, Deiters’ group have screened 1364 compounds in a cellular assay based on luciferase expression and selective small molecule inhibitors of miRNA-21 and miRNA-122, as well as a selective activator of miRNA-122 have been identified. All these studies confirmed that in fact, miRNAs are high-value “druggable” targets that can also be selectively modulated. Our preliminary data suggest that a set of miRNAs are dysregulated both in a transgenic mouse model of MJD and in neuronal cells derived from iPSCs of MJD patients, which foresees a relevant role for these miRNAs in MJD pathology. Therefore, our aim in this project is to identify promising miRNA-specific small molecules capable of selectively modulate miRNA levels in order to readjust miRNA dysregulated levels in MJD models and test their therapeutic potential in MJD. Overall, taking advantage of the possibility of modulating miRNA levels using FDA-approved drugs that could function as miRNA-specific drug activators/inhibitors we intend to develop a promising therapeutic approach to MJD, and eventually possible to be applied in other SCAs.
In this project we aim to explore the potential of a specific-miRNA small molecule intervention in the reversion of miRNA misregulation as a relevant therapeutic approach to MJD, and eventually to other SCAs.