The bench to bedside journey of tricyclo-DNA antisense oligonucleotides for the treatment of Duchenne muscular dystrophy.

The development of antisense oligonucleotide (ASO)-based therapeutics has made tremendous progress over the past few years, in particular for the treatment of neuromuscular disorders such as Duchenne muscular dystrophy and spinal muscular atrophy. Several ASO drugs have now reached market approval for these diseases and many more are currently under clinical evaluation. Among them, ASOs made of the tricyclo-DNA originally developed by Christian Leumann have shown particularly interesting properties and demonstrated promise for the treatment of Duchenne muscular dystrophy.

Oligonucleotide Enhancing Compound Increases Tricyclo-DNA Mediated Exon-Skipping Efficacy in the Mdx Mouse Model.

Nucleic acid-based therapeutics hold great promise for the treatment of numerous diseases, including neuromuscular disorders, such as Duchenne muscular dystrophy (DMD). Some antisense oligonucleotide (ASO) drugs have already been approved by the US FDA for DMD, but the potential of this therapy is still limited by several challenges, including the poor distribution of ASOs to target tissues, but also the entrapment of ASO in the endosomal compartment. Endosomal escape is a well recognized limitation that prevents ASO from reaching their target pre-mRNA in the nucleus.

How HIV-1 Integrase Associates with Human Mitochondrial Lysyl-tRNA Synthetase.

Replication of human immunodeficiency virus type 1 (HIV-1) requires the packaging of tRNA from the host cell into the new viral particles. The GagPol viral polyprotein precursor associates with mitochondrial lysyl-tRNA synthetase (mLysRS) in a complex with tRNA, an essential step to initiate reverse transcription in the virions. The C-terminal integrase moiety of GagPol is essential for its association with mLysRS.