Collagen VI-related dystrophies (COL6-RD) are a group of rare muscular dystrophies that typically manifest with muscle weakness, joint contractures as well as joint hyperlaxity, and respiratory insufficiency of variable severity. COL6-RDs are caused by pathogenic variants in the collagen VI genes. Our prior studies have shown altered levels of transforming growth factor beta (TGFβ) signaling in muscle biopsies of patients with COL6-RDs. To gather more insight into the mechanism of disease and identify therapeutic targets, we have generated and studied a new mouse model of COL6-RDs based on a homozygous deletion of the Col6a2 gene. Col6a2-/- mice show muscle weakness, atrophy, and fibrosis, although these findings are less severe compared to patients with similar mutations. Col6a2-/- mice also show altered TGFβ pathway signaling in their muscle tissue, similar to the patient muscle biopsies. In this study, we test the effect of TGFβ pathway inhibition in Col6a2-/- mice. We designed splice-switching antisense oligonucleotides (PMOs) that target the TGFβ receptor 1 (Tgfbr1) pre-mRNA, resulting in an internally deleted protein, with a dominant negative effect on the receptor complex, and thus inhibit TGFβ signaling. In vitro administration of the lead PMO in C2C12 and MEF cell lines and in vivo intramuscular injections of the PMO in our mouse model confirmed the intended exon skipping. Long-term (12-week) studies of the PMO via tail vein injection in Col6a2-/- mice and controls are ongoing to identify an optimal dose, confirm the effects of the PMO on TGFβ activity in muscle tissue, and evaluate its preliminary efficacy on the Col6a2-/- mouse phenotype. These studies pave the way for future proof of concept preclinical, efficacy studies that target the TGFβ pathway in COL6-RDs.