Fig. 4 |. Efficient in vivo delivery of PPMO to murine vascular cells and tissues.

a, The EGFP-654 splicing assay demonstrates efficient in vivo delivery of PPMOs to murine vascular cells and tissues. The schematic of the EGFP-654 reporter system illustrates that the mutation at nucleotide 654 of the intron results in partial intronic retention in spliced mRNA and prevention of proper translation of EGFP. The targeted PPMO blocks the aberrant splice site and restores proper splicing allowing for EGFP expression. b, Immunohistochemical analysis of sectioned ascending aortas after intravenous injection of EGFP-654 PPMO into reporter mice demonstrates restored expression of EGFP in VSMCs. Saline served as the negative control. Two mice (one male, one female) were injected in a single experiment and eight sections per aorta were analyzed. c–e, Single-dose pharmacodynamic analysis of SRP-2001 was performed on female and male mice expressing two copies of the human LMNA transgene harboring the classic HGPS mutation, G608G (LMNA^G/G). The efficacy of intravenous drug delivery was determined by comparing progerin transcripts and PPMO levels in the aorta (c), heart (d) and kidney (e) after single intravenous doses of 60 mg kg⁻¹. Values and error bars represent the mean ± s.d. for n = 6 per treatment group.