TIMP-1 and CKM as Novel Noninvasive Serum Biomarkers of Therapeutic Response for Exon-Skipping Therapies in Duchenne Muscular Dystrophy


Clinical Trials

Poster Number: Virtual


Peter Burch, PhD, Sarepta Therapeutics, Inc., Amy Erickson, Sarepta Therapeutics, Inc., Marie Claire Mukashyaka, MS, Sarepta Therapeutics, Inc., Leslie CL Wu, Sarepta Therapeutics, Inc., Jianbo Zhang, Sarepta Therapeutics, Inc., Kristin Ha, Sarepta Therapeutics, Inc., Jenna Wood, Sarepta Therapeutics, Inc., Sam Foley, Sarepta Therapeutics, Inc., Bryan Mastis, Sarepta Therapeutics, Inc., Nino Jungels, Sarepta Therapeutics, Inc., Bridge Hunter, Sarepta Therapeutics, Inc., John R Hadcock, Sarepta Therapeutics, Inc.

Background: Peptide-conjugated PMOs (PPMOs) are a next-generation chemistry platform in which a cell-penetrating peptide is conjugated to the PMO backbone, with the goal of increasing cellular uptake, exon skipping, and dystrophin production. Tissue inhibitor of metalloproteinases-1 (TIMP-1) and creatine kinase muscle type (CKM) serum levels are elevated in patients with DMD and in the mdx mouse model of DMD and correlate with disease severity.
Objective: We assess the utility of TIMP-1 and CKM as serum biomarkers of response to PPMO in mdx mice.
Methods: Mdx mice were injected intravenously every 4 weeks (Q4W) for 24 weeks with vehicle or RC-1001, a PPMO targeting the mdx mutation (exon 23), at doses of 20, 40 or 80 mg/kg (N=6 mice per group). Exon 23 skipping and dystrophin protein expression were assessed by droplet digital polymerase chain reaction and western blot respectively. Grip strength was also measured. TIMP-1 and matrix metallopeptidase 9 (MMP9) serum levels were measured by ELISA; CKM serum levels were measured by Meso Scale Discovery electrochemiluminescence assay.
Results: Single dose of RC-1001 resulted in sustained concentration-dependent exon 23 skipping and dystrophin protein increase up to 24 weeks with Q4W dosing; grip strength also improved throughout the study. Single dose RC-1001 40 mg/kg significantly decreased TIMP-1 (<2000 pg/ml; P < 0.0001) and CKM (<10 ?g/ml; P = 0.044) levels but not MMP9, demonstrating biomarker response specificity. Q4W dosing resulted in sustained concentration-dependent decrease in TIMP-1 and CKM levels, but not MMP9, throughout 24 weeks. Increased grip strength correlated in a dose-dependent manner with decreased TIMP-1 (r = -0.74; P = 0.0003) and CKM (r = -0.69; P = 0.0007) levels as early as after one administration of the PPMO.
Conclusions: These data support further investigation of TIMP-1 and CKM as potential noninvasive biomarkers of therapeutic response for exon-skipping therapies for DMD.