ATL1102 is an antisense (ASO) inhibitor of human CD49d, alpha-chain of adhesion molecule VLA-4. ATL1102 reduced blood CD49d+ immune cells producing promising six-month phase-2 results in non-ambulant patients with DMD; stabilizing upper limb PUL2.0 function, MRI fat fraction, and strength measurements compared to worsening with steroids.
ASO to mouse CD49d (ISIS348574) was used in combination with a dystrophin morpholino exon 23 skipping restoration drug (PMO). Mice were treated once weekly for 8 weeks with ASO, control mismatch oligonucleotide, saline, or PMO drug alone for 4 weeks, and PMO in combination with either ASO or mismatch. Only ASO+PMO demonstrated a relative increase to saline mice in the specific maximum force and eccentric muscle force in the exterior digitorum longus (EDL) muscle after 1 and 5 muscle eccentric contractions. After 10 contractions ASO+PMO was superior also to PMO monotherapy but not ASO monotherapy, PMO monotherapy was superior only relative to saline and ASO monotherapy superior to both saline and mismatch controls.
Quadricep muscle RNA was prepared from the above groups and wild-type mice (n=6/group) and RNA-sequencing used to evaluate gene expression. Filtering out low-expressing genes <1 Count/Million, differential expression analysis was done in R, with p values adjusted using the Benjamini-Hochberg false discovery rate (FDR), Bayesian adjusted to <0.05. ASO monotherapy showed 2 unique transcripts, TRDN and GM2a and none in PMO or control monotherapy vs mdx saline. 52 transcripts, most unique to the ASO+PMO treatment versus mdx saline (2* also in ASO FDR<0.06) were found. The affected targets were involved in immune response (BTLA*, PPML1, TNFSM13), lipolysis (FAPBP4*, G0S2), fibrosis (IGFBP-7, Calu), muscle cell (ASB15) and muscle stem cell function (ADAM10, Mt-Tp, MyoM1). These genes can play roles in EDL muscle function improvement in mdx mice treated with ASO+PMO and pathways support the rationale for ATL1102 combination therapy in DMD patients.