Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons

Pietro Giuseppe Mazzara, Sharon Muggeo, Mirko Luoni, Luca Massimino, Mattia Zaghi, Parisa Tajalli-Tehrani Valverde, Simone Brusco, Matteo Jacopo Marzi, Cecilia Palma, Gaia Colasante, Angelo Iannielli, Marianna Paulis, Chiara Cordiglieri, Serena Gea Giannelli, Paola Podini, Cinzia Gellera, Franco Taroni, Francesco Nicassio, Marco Rasponi and Vania Broccoli ()
Additional contact information
Pietro Giuseppe Mazzara: San Raffaele Scientific Institute
Sharon Muggeo: San Raffaele Scientific Institute
Mirko Luoni: San Raffaele Scientific Institute
Luca Massimino: San Raffaele Scientific Institute
Mattia Zaghi: San Raffaele Scientific Institute
Parisa Tajalli-Tehrani Valverde: San Raffaele Scientific Institute
Simone Brusco: San Raffaele Scientific Institute
Matteo Jacopo Marzi: Istituto Italiano di Tecnologia (IIT)
Cecilia Palma: Politecnico di Milano
Gaia Colasante: San Raffaele Scientific Institute
Angelo Iannielli: San Raffaele Scientific Institute
Marianna Paulis: Humanitas Clinical and Research Center
Chiara Cordiglieri: National Institute of Molecular Genetics “Romeo e Enrica Invernizzi” - INGM
Serena Gea Giannelli: San Raffaele Scientific Institute
Paola Podini: San Raffaele Scientific Institute
Cinzia Gellera: Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta
Franco Taroni: Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta
Francesco Nicassio: Istituto Italiano di Tecnologia (IIT)
Marco Rasponi: Politecnico di Milano
Vania Broccoli: San Raffaele Scientific Institute

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Friedreich’s ataxia (FRDA) is an autosomal-recessive neurodegenerative and cardiac disorder which occurs when transcription of the FXN gene is silenced due to an excessive expansion of GAA repeats into its first intron. Herein, we generate dorsal root ganglia organoids (DRG organoids) by in vitro differentiation of human iPSCs. Bulk and single-cell RNA sequencing show that DRG organoids present a transcriptional signature similar to native DRGs and display the main peripheral sensory neuronal and glial cell subtypes. Furthermore, when co-cultured with human intrafusal muscle fibers, DRG organoid sensory neurons contact their peripheral targets and reconstitute the muscle spindle proprioceptive receptors. FRDA DRG organoids model some molecular and cellular deficits of the disease that are rescued when the entire FXN intron 1 is removed, and not with the excision of the expanded GAA tract. These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.

Date: 2020
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DOI: 10.1038/s41467-020-17954-3

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