Development of mutation-independent strategies to treat rare and common mitochondrial-associated disorders
Mitochondrial dysfunction underlies the pathogenesis of a variety of human neurodegenerative diseases, either directly, as in the case of the rare Mitochondrial Diseases (MDs), or indirectly, as in more common neurodegeneration, such as Parkinson’s diseases. In particular a tight connection between vision and mitochondrial dysfunction has been extensively described. Several MDs are associated with some form of visual impairment. In particular Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), the most frequent mitochondrial optic neuropathies (ONs), are both characterized by degeneration of retinal ganglion cells and loss of vision. Interestingly, also the most common ONs, such as glaucoma and diabetic retinopathy also show signs of mitochondrial dysfunction and share clinical similarities with the hereditary MDs. Despite a vast amount of research these pathologies are still only treated symptomatically, and, in this respect, mitochondria could represent the common denominator and hence a promising therapeutic target. We recently demonstrated that the microRNAs miR-181a and miR-181b (miR-181a/b) regulate key genes involved in mitochondrial biogenesis function and clearance. We also show that these miRNAs are involved in the global regulation of mitochondrial turnover in the central nervous system (CNS) through the coordination of mitochondrial biogenesis and mitophagy. Interestingly miR-181a/b downregulation protects neurons from cell death and ameliorates the disease phenotype in different in vivo models of MDs, including LHON.
The main interest of the lab is to develop and validate new therapeutic strategies enhancing mitochondrial turnover in the CNS to treat mitochondrial-associated neurodegeneration in a mutation-independent manner. Our strategies will be applied in models of rare diseases such as mitochondrial ONs, as well as in common disorders models such as glaucoma and Parkinson disease.
The main interest of the lab is to develop and validate new therapeutic strategies enhancing mitochondrial turnover in the CNS to treat mitochondrial-associated neurodegeneration in a mutation-independent manner. Our strategies will be applied in models of rare diseases such as mitochondrial ONs, as well as in common disorders models such as glaucoma, Diabetic Retinopathy and Parkinson disease.
In addition, we are exploring novel genome editing approaches to develop mutation-independent strategies for mitochondrial ONs and genetic forms of glaucoma using cutting-edge in vitro models, i.e. patients-derived retinal organoids, and in vivo models.
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The overall goal of my research is to find effective treatments for defective mitochondrial functions. In particular we aim to develop mutation-independent strategies to treat rare and common mitochondrial-associated disorders.
Additional Funding
- MIC - MITOCON - INSIEME PER LO STUDIO E LA CURA DELLE MALATTIE MITOCONDRIALI ODV - miR-181a/b inhibition as new therapeutic strategy for Mitochondrial Optic Neuropath (2023-2026)
- MSAL (Italian Ministry of Health) - PNRR M6/C2_CALL 2023: THERAPY4ALL - Towards therapies for mitochondrial diseases. Funding period: 2024 - 2026
- AFM-Telethon - Strategic Project: miR-181a/b downregulation: a pan therapeutic approach to treat rare diseases associated with mitochondrial dysfunction. Funding period: 2025 - 2030.
- MUR (Italian Ministry of Universities and Research) - PRIN2022 PNRR: MitoTarget: Molecular and pharmacological approaches to target mitochondrial diseases. Funding period: 2023 - 2026.
- MUR, PRIN2022: “Entrapping gene expression to optimize therapeutic window of gene therapy products. 244.963 €; Funding period: 2023 - 2026.