An anti-sense oligonucleotide efficiently suppresses splicing of an alternative exon in vascular smooth muscle in vivo

This study aimed to develop a gene-based therapy to suppress splicing of Mypt1 E24 thereby switching MP enzyme to the NO-responsive isoform. CRISPR/Cas9 constructs were effective at editing of Mypt1 E24 in vitro, however targeting of vascular smooth muscle in vivo with AAV9 was inefficient. In contrast an octo-guanidine conjugated anti-sense oligonucleotide targeting the 5' splice site of Mypt1 E24 was highly efficient in vivo. It reduced the percent splicing inclusion of Mypt1 E24 from 80 to 10% in mesenteric arteries. The maximal and half-maximal effects occurred at 12.5 and 6.25 mg/kg, respectively. The effect persisted for at least one month without toxicity. This highly effective splice blocking anti-sense oligonucleotide could be developed as a novel therapy to reverse vascular dysfunction common to diseases such as hypertension and heart failure.PMID:38276948 | DOI:10.1152/ajpheart.00745.2023

Source: American Journal of Physiology. Heart and Circulatory Physiology - January 26, 2024 Category: Physiology Authors: Celio Damacena de Angelis Mariam Meddeb Nelson Chen Steven A Fisher Source Type: research