Cell-resolved pharmacodynamic profiling reveals tissue- and cell-population-specific activity of antisense oligonucleotide chemical conjugates in vivo

Palmitate-conjugated antisense oligonucleotides show the broadest extrahepatic Malat1 knockdown and pronounced whole-tissue activity in heart and skeletal muscle in PDGFR-eGFP mice.

• Why it matters: Whole-tissue pharmacodynamic readouts can miss which cell populations actually take up and respond to ASO conjugates, limiting organ-specific optimization.
• What they did: In PDGFR-eGFP reporter mice, Malat1 knockdown was measured after subcutaneous ASO dosing in whole tissues and in cell-sorted PDGFR+/GFP versus PDGFR-/GFP- populations.
• The result: Cell-resolved profiling revealed preferential palmitate-ASO activity within PDGFR skeletal-muscle populations and showed conjugate-dependent safety signals, including body-weight loss and ALT elevation with tocopherol-ASO in male mice.

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