Artificial microRNA suppresses C9ORF72 variants and decreases toxic dipeptide repeat proteins in vivo.
Gabriela Toro CabreraKatharina E MeijboomAbbas AbdallahHelene TranZachariah W FosterAlexandra WeissNicholas WightmanRachel StockTania GendronAlisha GruntmanAnthony GiampetruzziLeonard PetrucelliRobert H BrownChristian MuellerPublished in: Gene therapy (2023)
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons, causing progressive muscle weakness and respiratory failure. The presence of an expanded hexanucleotide repeat in chromosome 9 open reading frame 72 (C9ORF72) is the most frequent mutation causing familial ALS and frontotemporal dementia (FTD). To determine if suppressing expression of C9ORF72 gene products can reduce toxicity, we designed a set of artificial microRNAs (amiRNA) targeting the human C9ORF72 gene. Here we report that an AAV9-mediated amiRNA significantly suppresses expression of the C9ORF72 mRNA, protein, and toxic dipeptide repeat proteins generated by the expanded repeat in the brain and spinal cord of C9ORF72 transgenic mice.
Keyphrases
- amyotrophic lateral sclerosis
- spinal cord
- copy number
- poor prognosis
- respiratory failure
- signaling pathway
- binding protein
- multiple sclerosis
- genome wide
- intensive care unit
- extracorporeal membrane oxygenation
- mechanical ventilation
- minimally invasive
- working memory
- neuropathic pain
- long non coding rna
- gene expression
- dna methylation
- small molecule
- drug delivery
- amino acid
- transcription factor
- subarachnoid hemorrhage
- induced pluripotent stem cells
- functional connectivity
- blood brain barrier
- protein protein