| Title: |
Drug delivery nanosystems for skeletal muscle treatment in myotonic dystrophy ; Nanosystèmes de délivrance de médicaments pour le traitement des muscles squelettiques dans la dystrophie myotonique |
| Authors: |
Repellin, Mathieu |
| Contributors: |
Laboratoire d'automatique, de génie des procédés et de génie pharmaceutique (LAGEPP); Université Claude Bernard Lyon 1 (UCBL); Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Centre National de la Recherche Scientifique (CNRS); Université de Lyon; Università degli studi (Vérone, Italie); Stéphanie Briançon; Manuela Malatesta; Giovanna Lollo |
| Source: |
https://theses.hal.science/tel-04496909 ; Bioengineering. Université de Lyon; Università degli studi (Vérone, Italie), 2022. English. ⟨NNT : 2022LYSE1147⟩. |
| Publisher Information: |
CCSD |
| Publication Year: |
2022 |
| Collection: |
HAL Lyon 1 (University Claude Bernard Lyon 1) |
| Subject Terms: |
Nanoparticles; Muscles; Gene delivery; Dystrophy; Dystrophie; Thérapie génique; Muscle; Nanoparticules; [SDV.IB]Life Sciences [q-bio]/Bioengineering |
| Description: |
Myotonic dystrophy type 1 (DM1) is a genetic disorder of autosomal inheritance, characterized by progressive myopathy, myotonia and multiorgan involvement. This most common adult dystrophy is caused by an abnormal expansion of a trinucleotide repeat located on the DMPK gene. Experimental evidences support that pathogenesis of DM1 is caused by an RNA gain-of-function of the transcribed RNA from these mutant repeats, altering activities of several splicing regulators. Currently, no cure to treat the pathological mechanism of DM1 has reached the market. Although some molecules or nucleic acid-based strategies have been proposed in a context of drug repurposing or gene therapy, important drawbacks remain related to their effective delivery. To this end, nanomedicine represents a suitable non-viral approach to provide long-term treatments with a safe and efficient biodistribution profile. Therefore, the research project of this thesis was to set up experimental therapeutic strategies based on biocompatible nanocarriers to safely and efficiently deliver therapeutic agents in muscle cells. In this purpose, two different therapeutic strategies effective at different levels of the pathological mechanism of DM1 have been investigated. Firstly, the encapsulation of a small molecule, pentamidine, using hyaluronic acid-based nanocarriers has demonstrated an efficient internalization in murine muscle cells and murine muscle fibers while reversing pathological features in a DM1 cell model. Then, the investigations on lipid-based nanoparticles as nucleic acid carriers for enabling nucleic acid delivery has demonstrated the high efficiency of such nanosystems in murine and human muscle cells. Finally, preliminary data showed the efficient association of an antisense oligonucleotide sequence for treating the pathological mechanism of DM1, holding promises for further investigations in DM1 cell and animal models. Overall, the present work may pave the way to novel strategies to tackle the unmet therapeutic need in DM1 to halt the ... |
| Document Type: |
doctoral or postdoctoral thesis |
| Language: |
English |
| Relation: |
NNT: 2022LYSE1147 |
| Availability: |
https://theses.hal.science/tel-04496909; https://theses.hal.science/tel-04496909v1/document; https://theses.hal.science/tel-04496909v1/file/TH2022REPELLINMATHIEU.pdf |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.6792FF8E |
| Database: |
BASE |