The myotonic dystrophy type 1 drug development pipeline: 2022 edition

Cas9 nickase-mediated contraction of CAG/CTG repeats at multiple disease loci

“…A gene editing approach would have several advantages over more traditional approaches, including antisense oligonucleotides and microRNAs, which reduce the amount of HTT or DMPK mRNA 4,60 . Specifically, our gene editing approach would permanently improve the most proximal cause of the disease by reducing the size of the expanded CAG/CTG repeat.…”

“…The heterozygous expansion of CAG/CTG repeats at 15 different loci in the genome causes clinically distinct neurodegenerative and neuromuscular disorders, including Huntington’s disease (HD) and myotonic dystrophy type 1 (DM1) 1,2 . They are all currently without a disease modifying treatment 3,4 . The size of the expanded repeat tract explains up to 60% of the variation in the age at disease onset in HD 5 , with longer repeats leading to more severe phenotypes.…”

Recent Progress of Small Interfering RNA Delivery on the Market and Clinical Stage

“…97 AOC 1001, comprised of α TfR, a noncleavable linker, and siRNA targeting myotonin-protein kinase (DMPK), is designed for the treatment of myotonic dystrophy type 1 (DM1). The results of AOC 1001 in Phase 1/2 (NCT05027269) revealed successful delivery of RNA to the muscle 99 and DMPK mRNA decreased by approximately 42% following one or two doses. 100 Avidity also led the Phase 1/2 clinical trials for AOC 1044 and AOC 1020.…”

Revival of Bioengineered Proteins as Carriers for Nucleic Acids

“…56,57 Since 2022, various AOCs entered phase 2 clinical trials for a variety of indications, such as myotonic dystrophy type 1. 58,59 The principle of targeting carriers via antibodies and receptor-specific peptides is not limited to the delivery of oligonucleotides. Incorporation of these targeting moieties also showed increased cellular uptake and cell specificity for protein-based DNA and mRNA carriers.…”

“…One of the most straightforward nucleic acid delivery methods is through antibody-oligonucleotide conjugates (AOCs). The simplicity of AOCs makes them readily adaptable, while the pool of available antibodies continuously expands. , Since 2022, various AOCs entered phase 2 clinical trials for a variety of indications, such as myotonic dystrophy type 1. , The principle of targeting carriers via antibodies and receptor-specific peptides is not limited to the delivery of oligonucleotides. Incorporation of these targeting moieties also showed increased cellular uptake and cell specificity for protein-based DNA and mRNA carriers. − To enable cytoplasmic delivery multiple studies exploited the ability of pore-forming proteins to connect the endosomal lumen to the cytosol. ,, For example, Wittrup et al, employed pore-forming perfringolysin O (PFO) as a potent endosomal escape agent in their protein-based siRNA carrier .…”