Abstract

Antisense oligonucleotides (ASO) hold promise for therapeutic splice-switching correction in many genetic diseases; however, despite advances in chemistry and design, systemic use of ASOs is still limited due to poor tissue/cellular uptake. This talk will describe the therapeutic potential of ASOs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake in many tissues after systemic administration. These outstanding properties have been demonstrated in different mouse models of genetic diseases such as Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA). DMD is a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. While current naked ASOs do not significantly enter the heart or cross the blood brain barrier, systemic delivery of tcDNA-ASOs allow high levels of dystrophin rescue in skeletal muscles as well as in heart and to a lower extent in the brain. Moreover, we recently developed a new generation of PS-free tcDNA-ASO, conjugated to a lipid, displaying a much higher therapeutic index and safer toxicological profile. We are also evaluating direct injection of this compound in the CNS and we demonstrated for the first time the possibility to restore some of the cognitive defects associated with the lack of dystrophin in the brain of DMD mouse models. A clinical trial evaluating this new generation of conjugated tcDNA-ASO in DMD patients will be initiated shortly.