Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease

Abstract

Alternative splicing of pre-mRNA contributes strongly to the diversity of cell- and tissue-specific protein expression patterns. Global transcriptome analyses have suggested that >90% of human multiexon genes are alternatively spliced. Alterations in the splicing process cause missplicing events that lead to genetic diseases and pathologies, including various neurological disorders, cancers, and muscular dystrophies. In recent decades, research has helped to elucidate the mechanisms regulating alternative splicing and, in some cases, to reveal how dysregulation of these mechanisms leads to disease. The resulting knowledge has enabled the design of novel therapeutic strategies for correction of splicing-derived pathologies. In this review, we focus primarily on therapeutic approaches targeting splicing, and we highlight nanotechnology-based gene delivery applications that address the challenges and barriers facing nucleic acid-based therapeutics.

Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer

“…Targeting splicing mechanisms represents an emerging therapeutic possibility for several human diseases, including cancer [ 157 , 197 , 198 ]. Common approaches include RNA editing through single-stranded DNA molecules and the use of small-molecule compounds acting on splicing factors’ functions [ 198 ].…”

“…Targeting splicing mechanisms represents an emerging therapeutic possibility for several human diseases, including cancer [ 157 , 197 , 198 ]. Common approaches include RNA editing through single-stranded DNA molecules and the use of small-molecule compounds acting on splicing factors’ functions [ 198 ]. Antisense oligonucleotides (ASOs), called splice-switching oligonucleotides (SSOs), promote exon skipping or inclusion by binding to the complementary target pre-mRNAs [ 198 ].…”

Therapeutic Modulation of RNA Splicing in Malignant and Non-Malignant Disease

“…Improved understanding of splicing in disease pathogenesis, coupled with advances in nucleic acid-based therapeutics, have rendered splicing a promising therapeutic target. Consequently, strategies to activate or inhibit splicing have been implemented for therapeutic purposes (as recently reviewed [28]). We focus here on the use of antisense oligonucleotide (ASO) approaches and small molecules for modulating splicing.…”

Rescue of common exon‐skipping mutations in cystic fibrosis with modified U1 snRNAs

“…With 10 mutations and five exons analyzed, it is the first time that an exon rescue strategy is shown to work efficiently in a single gene on several exon‐skipping mutations and different exons. Additional strategies to correct exon skipping defects include antisense oligonucleotides (ASO) and chemical compounds (Suñé‐Pou et al, 2020). In general, the ASO based approach for rescuing exon skipping defects is based on the identification of appropriate splicing regulatory elements and thus more time consuming and expensive, and not easy testable on several splicing defects.…”