Group Leader: Germana Falcone
Topics : Muscle Biology and Pathology
Keywords: muscle biopathology, nocoding RNAs, gene therapy

Our research group has a wide long-standing experience in molecular and cellular biology of muscle cells, intracellular cell signaling in oncogenic transformation and differentiation, and post-transcriptional regulation of gene expression, particularly microRNA analysis and studies on microRNA-target interaction.

In past years our research has focused on the role of noncoding RNAs in normal muscle differentiation and in disease. Thanks to the development of a method to select and identify the functionally active microRNAs and their target mRNAs, we have identified some crucial microRNAs involved in normal muscle differentiation and in muscular dystrophies, particularly in Myotonic Dystrophy type 1 (DM1). In addition to microRNAs, we have also identified circular RNAs specifically upregulated in DM1. Both classes of noncoding RNAs are most likely involved in DM1 pathogenetic mechanisms and can be used as disease biomarkers. Functional characterization of DM1-related microRNAs and circular RNAs is a topic of ongoing research in our group.

DM1 is a dominantly inherited multisystemic disorder and the most common form of muscular dystrophy in adults. Especially in the most severe forms, life expectancy and quality in DM1 affected individuals are seriously compromised. The disease is caused by expanded CTG repeats in the 3’ untranslated region (3’UTR) of the DMPK gene. No effective therapy is yet available for DM1. Very recently, we have developed a CRISPR/Cas9-mediated genome editing approach for permanent deletion of pathogenetic repeats, using cell models ad hoc generated from DM1 patients’ biopsies. By using this strategy, we obtained a time-controlled and target-specific gene editing, and succeeded in reversing the pathologic phenotype of DM1 cells. We are now applying this gene editing approach to a mouse model of DM1 with the ultimate goal to obtain the reversal of the diseased phenotype, opening the way for future gene therapy application in humans.

 External Collaborators:

  • Fabio Martelli, Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, San Donato Milanese, Milano
  • Geneviève Gourdon, Centre de Recherche en Myologie, UMR 974, INSTITUT de MYOLOGIE, G.H. Pitié-Salpétrière, Paris, France

Key Pubblications

  1. Golini E, Rigamonti M, Raspa M, Scavizzi F, Falcone G, Gourdon G, Mandillo S (2023) Excessive rest time during active phase is reliably detected in a mouse model of Myotonic Dystrophy type 1 using home cage monitoring. Behav. Neurosci. 2023, 17:1130055. doi: 10.3389/fnbeh.2023.1130055
  2. Cifola I, Fratini F, Cardinali B, Palmieri V, Gatti G, Selmi T, Donzelli S, Sacconi A, Cesarini V, Marei HE, Papi M, Blandino G, Cenciarelli C, Falcone G, D’Agnano I (2022) miRnome and Proteome Profiling of Small Extracellular Vesicles Secreted by Human Glioblastoma Cell Lines and Primary Cancer Stem Cells. Biomedicines 2022, 10, 1886. doi: 10.3390/biomedicines10081886.
  3. Izzo M, Battistini J, Provenzano C, Martelli F, Cardinali B, Falcone G. (2022) Molecular Therapies for Myotonic Dystrophy Type 1: From Small Drugs to Gene Editing. Int J Mol Sci. 2022, 23, 4622. Doi: 10.3390/ijms23094622. Review.
  4. Cardinali B, Provenzano C, Izzo M, Voellenkle C, Battistini J, Strimpakos G, Golini E, Mandillo S, Scavizzi F, Raspa M, Perfetti A, Baci D, Lazarevic D, Garcia-Manteiga JM, Gourdon G, Martelli F, Falcone G. (2021) Time-controlled and muscle-specific CRISPR/Cas9-mediated deletion of CTG-repeat expansion in the DMPK Mol Ther Nucleic Acids. 2021 Nov 29;27:184-199. doi: 10.1016/j.omtn.2021.11.024. eCollection 2022 Mar 8.PMID: 34976437 
  5. Ondono R, Lirio Á, Elvira C, Álvarez-Marimon E, Provenzano C, Cardinali B, Pérez-Alonso M, Perálvarez-Marín A, Borrell JI, Falcone G, Estrada-Tejedor R. (2020) Design of novel small molecule base-pair recognizers of toxic CUG RNA transcripts characteristics of DM1. Comput Struct Biotechnol J. 2020 Dec 6;19:51-61. doi: 10.1016/j.csbj.2020.11.053. eCollection 2021.
  6. Guglielmi L, Nardella M, Musa C, Cifola I, Porru M, Cardinali B, Iannetti I, Di Pietro C, Bolasco G, Palmieri V, Vilardo L, Panini N, Bonaventura F, Papi M, Scavizzi F, Raspa M, Leonetti C, Falcone G, Felsani A, D’Agnano I. (2020) Circulating miRNAs in Small Extracellular Vesicles Secreted by a Human Melanoma Xenograft in Mouse Brains. Cancers (Basel). 2020 Jun 19;12(6):1635. doi: 10.3390/cancers12061635.
  7. Voellenkle C, Perfetti A, Carrara M, Fuschi P, Renna LV, Longo M, Sain SB, Cardani R, Valaperta R, Silvestri G, Legnini I, Bozzoni I, Furling D, Gaetano C, Falcone G, Meola G, Martelli F (2019) Dysregulation of Circular RNAs in Myotonic Dystrophy Type 1. Int J Mol Sci. 2019 Apr 19;20(8). pii: E1938. doi: 10.3390/ijms 20081938.

Research Group

 

Beatrice Cardinali (researcher)
+39 90091322  

Claudia Provenzano (researcher)
+39 90091474

Collaborators
Silvia Mandillo(researcher)
Elisabetta Golini (researcher)
Georgios Strimpakos (researcher)

Programs & resourcers

2020 – 2024   
Partner, AFM Grant 23054: Circular RNA role in Myotonic Dystrophy type 1

2019 – 2023           
Coordinator, TELETHON Italy Grant GGP19035: Gene editing in Myotonic Dystrophy type 1: assessment of efficiency, safety and therapeutic effect of CTG-repeat deletion in a mouse model of disease (https://www.telethon.it/en/what-we-do/research/)

2017 – 2018
Partner, CNR Flagship Project InterOmics: Integration of exosome miRNome/proteome Signature for identification of specific Glioblastoma biomarkers (https://www.cnr.it/it/news/7390/2th-call-for-proposals-bando-progetto-bandiera-interomics-2017)

2015 – 2018
Partner, AFM Grant 18477: MicroRNA function and use as biomarkers in Myotonic Dystrophy type 1 (http://www.afm-telethon.com/research.html)

2015 – 2016
Partner, CNR Flagship Project InterOmics: miRNome analysis and functional studies of cancer cell-released exosomes in experimental models of Glioblastoma (https://www.cnr.it/it/news/5952/call-for-proposals-progetto-bandiera-interomics)