| Authors | MiRNAs negatively regulated in PD | Target genes | Molecular mechanisms | Ethics and the use of miRNAs in gene therapy |
| McMillan et al., 2017 [63] | miR-7 | SNCA | MiR-7 is responsible for down-regulating SNCA gene expression, its depletion being associated with α -Syn accumulation and neuronal loss. | The current technology for obtaining exosomes needs to be improved in order to obtain purer exosomes: technologies for their purification and enrichment are still fairly rudimentary.
Another reasonable concern stems from quality control of exosome purity, which remains an open challenge: there is no candidate protein that is a unique and specific marker for exosomes.
Until recently, the most common method for loading miRNAs or siRNAs into exosomes was electroporation. Although this strategy has proved effective for loading siRNAs into purified exosomes, unfortunately, transfection of exosomes directly with nucleic acid using this system is not entirely efficient, as it requires both separation and purification of exosomes before and after transfection, thus drastically reducing the quantity of exosomes.
Another limitation of exosomes is that they are usually obtained in small yields.
Exosomes cannot be stored for long periods. Consequently, there is also a need to improve exosome preservation technology to protect their biological activities and make them suitable for clinical application.
Thus, the use of microRNAs in gene therapy can damage the human organism. Their use in gene therapy therefore requires caution and scrupulous respect for the ethical principles of precaution and the fundamental bioethical principles of beneficence and non-maleficence: “Primum, non nocere”! |
| Zhang et al., 2018 [37] | miR-21 | PTEN | MiR-21 enhances neuronal plasticity and cell survival. | |
| Asadi et al., 2023 [64] | miR-873 | ABCA1 | MiR-873 is able to reduce PD symptoms by up-regulating ABCA1 and A20. Inhibition of miR-873 may play a dual protective role in PD by inducing intracellular cholesterol homeostasis and ameliorating neuroinflammation. | |
| Straniero et al., 2017 [65] | miR-22-3p | ACS | MiR-22-3p controls GBA. | |
| Doxakis et al., 2010 [66] | miR-153 | SNCA | MiR-153 is responsible for down-regulation of SNCA gene expression, its depletion inducing α-Syn accumulation and neuronal loss. | |
| Miñones- Moyano et al., 2011 [67] | miR-34b/c | SNCA, Parkin et DU-1 | MiR-34b/c is responsible for the down-regulation of SNCA gene expression, its depletion leading both to the deposition of α -Syn in PD brain tissue and to the down-regulation of Parkin and DJ-1 gene expression. | |
| Kim et al., 2007 [68] | miR-133b | Pitx3 | MiR-133b is specifically expressed in the midbrain, where it regulates both the maturation and function of midbrain DA neurons, its depletion being associated with a massive loss of DA neurons. | |
| Soreq et al., 2011 [69] | miR-124 | Calpain 1, Bim, STAT3, Annexine A5, MEKK3 | MiR-124 regulates synapse morphology, neurotransmission, inflammation, autophagy and mitochondrial function, its depletion being implicated in major pathophysiological mechanisms. | |
| Chen et al., 2017 [70] | miR-4639-5p | DJ-1 | MiR-4639-5p negatively regulates DJ-1 post-transcription levels, its up-regulation being responsible for massive induction of oxidative stress and, consequently, neuronal death. | |
| Jiang et al., 2019 [71] | miR-137 | OXR1 | MiR-137 is involved in the induction of oxidative stress in neurons, its up-regulation being implicated in a massive induction of oxidative stress and neuronal death |