FRRB Project 1740526 - Precision Medicine Applied to Leigh Syndrome at different stages: development of a Neonatal metabolic supplementation and a fetal gene THERapy approach.
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Name and Surname of PI |
Dario Brunetti |
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Project Acronym |
PANTHER |
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Project ID |
1740526 |
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Host Institution |
Fondazione IRCCS Istituto Neurologico Carlo Besta - Milan |
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Pathology of Interest |
Leigh Syndrome |
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Research Area |
Rare Diseases |
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Project Start Date |
16 July 2021 |
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Project End Date |
15 July 2024 |
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Funding |
€ 557.800,00 |
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Type of Project |
Individual |
PROJECT SUMMARY
Surf1 mutations represent the main cause of Leigh syndrome (LS), a rare neurometabolic genetic disease with onset in the first months of life that causes severe neuromuscular disabilities and patient death in the first three years of life. Surf1 is involved in the correct functioning of mitochondria, the energy plants of the cell. We have recently developed sophisticated preclinical models both in vitro (brain organoids from patient cells) and in vivo (Surf1KO pigs) which have allowed us to understand that SURF1 mutations cause a metabolic block of the cell which hinders the correct differentiation of neurons during neurodevelopment. During last two years of the PANTHER project, we have used these models to develop:
1) a Neonatal Metabolic Therapy, aimed at restoring cellular metabolism during postnatal neurodevelopment.
2) an In Utero Fetal Gene Therapy, aimed at restoring the expression of the Surf1 gene in the prenatal phase.
During the first year of activity, we tested the effectiveness of a modulator of mitochondrial metabolism (PD-0E7) on 2D in vitro systems (differentiating neural precursors- NPC). This compound was effective in increasing oxidative phosphorylation in treated cells, favoring the differentiation processes that are altered in Leigh syndrome.
During the second year we tested PD-0E7 on 3D in vitro systems (SURF1 mutated brain organoids). Also in this model, PD-0E7 resulted effective in promoting neurodifferentiation processes, preventing the structural alterations observed in untreated mutated organoids. We also tested the same compound on newborn pigs. Preliminary data obtained in vivo (although still preliminary) have highlighted an important effect of PD-0E7 on the improvement of the general health status of SURF1KO piglets. At the same time we were able to develop an efficient in vivo protocol for in utero fetal gene therapy.