Biology subjects

Frommer, J.

Publications and source records attributed to Frommer, J..

2 recordsLinked to original sources

bioRxiv2026

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

Chemical conjugation can modulate antisense oligonucleotide (ASO) pharmacology and improve organ-specific delivery, yet whole-tissue measurements provide limited information on cell-specific activity. Here, we used metastasis-associated lung adenocarcinoma transcript 1 (Malat1) knockdown as a pharmacodynamic readout to compare whole-tissue and cell-resolved activity of chemically conjugated ASOs in platelet-derived growth factor receptor alpha-enhanced green fluorescent protein (PDGFR-eGFP) mouse model to assess their in vivo uptake in PDGFR-expressing (GFP+) cells. This reporter mouse model uses PDGFR as an exemplar cellular marker and provides an accessible tool for evaluating ASO conjugate activity within mesenchymal stromal and progenitor populations, mainly tissue fibroblasts. Following subcutaneous administration, Malat1 was quantified in whole tissues and cell-sorted PDGFR+/GFP or PDGFR-/GFP- populations. ASO-mediated Malat1 reduction varied by tissue and conjugate chemistry, with palmitate conjugation producing the broadest extrahepatic activity and pronounced whole-tissue activity in heart and skeletal muscle. Cell-resolved analysis further revealed preferential palmitate-ASO activity within PDGFR skeletal-muscle populations. Preliminary safety assessment also showed conjugate-dependent differences, with body-weight loss and ALT elevation in tocopherol-ASO-treated male mice and spleen enlargement in both sexes. These findings present an in vivo modelling system for evaluating cell-specific ASO activity and demonstrate the advantages of cell-resolved assessment over whole-tissue measurements.

molecular biology↗

bioRxiv2026

The androgen receptor polyglutamine tract sets the transcriptional balance between muscle growth and atrophy

The androgen receptor (AR) mediates the potent anabolic effects of testosterone and other androgens on skeletal muscle, yet the transcriptional mechanisms coupling this hormonal signal to muscle growth remain unresolved. AR is a ligand-inducible transcription factor whose N-terminal transactivation domain (NTD) harbours a polymorphic polyglutamine (polyQ) tract that, when pathologically expanded, causes spinal and bulbar muscular atrophy (SBMA). To define how the NTD and its polyQ tract shape muscle transcription, we combined an engineered AR allelic series in human myogenic cells with super-resolution and single-molecule imaging, genome-wide binding and expression maps, and human population genetics. Under physiological conditions, androgen-activated AR assembles into dynamic transcriptional condensates and drives an anabolic programme in skeletal muscle through activation of the AP-1 pathway. Progressive expansion of the polyQ tract destabilises AR chromatin binding and shifts its occupancy from promoters to low-affinity distal enhancers, tracking with imaging signatures of muscle aging. In SBMA, this culminates in aberrant transactivation of ectodysplasin A2 receptor (EDA2R), a marker of senescence and inflammation, which engages non-canonical NF-{kappa}B signalling to drive muscle atrophy. Silencing Eda2r attenuated muscle wasting in SBMA mice, establishing this axis as therapeutically actionable. Together, these findings reveal a fundamental mechanism of skeletal-muscle homeostasis and open therapeutic avenues for the many conditions in which muscle atrophy is central.

molecular biology↗