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

P.G. Mazzara, S. Muggeo, M. Luoni, L. Massimino, M. Zaghi, P.T.-T. Valverde, S. Brusco, M.J. Marzi, C. Palma, G. Colasante, A. Iannielli, M. Paulis, C. Cordiglieri, S.G. Giannelli, P. Podini, C. Gellera, F. Taroni, F. Nicassio, M. Rasponi, V. Broccoli

Research output: Contribution to journalArticlepeer-review


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. © 2020, The Author(s).
Original languageEnglish
Article number4178
JournalNat. Commun.
Issue number1
Publication statusPublished - 2020


  • brain derived neurotrophic factor
  • cytochrome c oxidase
  • frataxin
  • genomic DNA
  • glial cell line derived neurotrophic factor
  • mitochondrial DNA
  • nestin
  • reelin
  • transcription factor Sox2
  • antioxidant
  • iron binding protein
  • transcriptome
  • cell
  • gene expression
  • genetic analysis
  • laboratory method
  • molecular analysis
  • muscle
  • pathology
  • RNA
  • sensory system
  • action potential
  • Article
  • ataxia
  • bioinformatics
  • cell culture
  • chromatin immunoprecipitation
  • coculture
  • controlled study
  • CRISPR Cas system
  • electron microscopy
  • Friedreich ataxia
  • gene deletion
  • gene editing
  • gene silencing
  • human
  • human cell
  • induced pluripotent stem cell
  • motoneuron
  • myelination
  • nanofabrication
  • nerve cell differentiation
  • nervous system development
  • neurite outgrowth
  • nonhuman
  • organoid
  • oxidative phosphorylation
  • phenotype
  • real time polymerase chain reaction
  • RNA sequence
  • sensory nerve cell
  • trinucleotide repeat
  • upregulation
  • Western blotting
  • whole cell patch clamp
  • cell differentiation
  • chromatin
  • drug effect
  • genetic predisposition
  • genetics
  • intron
  • metabolism
  • mitochondrion
  • procedures
  • sequence analysis
  • spinal ganglion
  • Antioxidants
  • Cell Differentiation
  • Chromatin
  • CRISPR-Cas Systems
  • Friedreich Ataxia
  • Ganglia, Spinal
  • Gene Editing
  • Genetic Predisposition to Disease
  • Humans
  • Induced Pluripotent Stem Cells
  • Introns
  • Iron-Binding Proteins
  • Mitochondria
  • Organoids
  • Sensory Receptor Cells
  • Sequence Analysis, RNA
  • Transcriptome


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