1. Gaining insights from transcriptomic signatures in spinal muscular atrophy : identification and exploration of new therapeutic targets
- Author
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Goli, Larissa, Lomonosova, Yulia, Wood, Matthew J. A., and Hammond, Suzan M.
- Subjects
RNA splicing ,Genetics ,Molecular biology ,Neuromuscular diseases - Abstract
5q-spinal muscular atrophy (SMA) is a rare, autosomal recessive, progressive, and lethal neuromuscular disease, most frequently of paediatric onset, caused by the loss of function of the survival of motor neuron (SMN1) gene. SMN1 codes for the SMN protein, whose best characterised role supports the biogenesis of the spliceosome and efficient splicing of pre- messenger RNAs. Twenty years of drug development have led to approval of three therapies in SMA, two of which are splice-switching therapies targeting the SMN2 paralog and disease- modifying gene to SMN1. The ceiling effect of splice-switching therapies as well as issues associated with the specialised delivery of oligonucleotide therapeutics in neurological use calls for research towards the identification and functional exploration of new therapeutic targets beyond SMN2 pre-mRNA. In this work, I explore three avenues for the identification of new therapeutic targets in SMA, using transcriptomics data in motor neurons (MN) and in skeletal muscle. First, I study time- and treatment- dependent genome-wide transcriptomic changes in neuronal tissues in a target-agnostic way and develop a proof-of-concept meta-analysis of all published human RNAseq data in neuronal tissues. In addition, I report a microarray dataset in laser-captured microdissected motor neurons from a severe (Taiwanese) mouse model and provide the first demonstration of neuronal transcriptome-wide efficacy of an intravenously administered splice-switching therapy. Secondly, I investigate the changes in the transcription of a rare subpopulation of RNAs, circular RNAs (circRNA), derived from the SMN1/2 loci. I show changes of expression of the most expressed SMN-derived circRNA, C2A-2B-3-4, in SMA fibroblasts, and provide computational evidence for their putative biological role. Finally, I design and develop two distinct pharmacological approaches to down-regulate FoxO3, a transcription factor transactivating the transcription of atrophy-inducing genes. I identify 8b2-(A) as a promising candidate for further in vitro development. This work provides new insights in the neurodegenerative processes in MN by tackling the first meta-analysis of published neuronal transcriptomics datasets in SMA, revealing methodological gaps in the study of circular RNAs in a high-isoform context, and identifying novel groups of genes dysregulated in early post-natal MN development in SMA. The identified targets can be further explored for therapeutic development in SMA and in other neurodegenerative and muscle- wasting conditions.
- Published
- 2022