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2.68eP Preclinical to human translation of regenerative index: quantification of progressive muscle degeneration and disease-modifying treatment response
Abstract   Peer reviewed

2.68eP Preclinical to human translation of regenerative index: quantification of progressive muscle degeneration and disease-modifying treatment response

Ryan Mitchell, Johnathan Smid, Charis McPherson, Shanti Rayagiri, Jacob Monast, Steven Moore, Frank Gleeson, Phil Lambert, Wildon Farwell and Michael Rudnicki
Neuromuscular disorders : NMD, Vol.67(Suppl 1), 106862
09/29/2026
DOI: 10.1016/j.nmd.2026.106862

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Abstract

Given the close relationship between muscle regeneration and damage, accurately quantifying muscle regeneration, particularly at a fiber level, is a significant challenge. We developed and validated an integrated histology-based Regeneration Index (RI) to assess and quantitate muscle regenerative capacity and monitor therapeutic response in clinical trials. Muscle biopsy samples were obtained from Duchenne canines, boys with confirmed Duchenne muscular dystrophy (DMD, ages 7-11 years) and age-matched controls. In preclinical experiments, DMD canines were dosed with SAT-3247 (inhibitor of AAK1 in satellite cells) between 9-13 months of age. Newly-formed fibers, identified by immunofluorescence of embryonic myosin heavy chains (eMHC), were normalized to necrotic immunoglobulin G (IgG)-positive fibers to calculate RI. In SAT-3247-treated DMD canines, RI was markedly increased from baseline in limb muscles and diaphragm and was accompanied by improved limb muscle contractile force, walking, and gait. In biopsies from DMD boys, the percent of eMHC+ fibers decreased sharply between ages 7-11, whereas the percent IgG+ fibers was oppositely increased resulting in a strong, significant negative correlation of RI with age (r= -0.888) despite stable myofiber morphology and satellite cell pool. Direct comparison revealed that RI in older (9-11 years) DMD boys was markedly lower than in younger (7-8 years) boys (p< 0.001). The RI approach of normalizing regeneration of new fibers to myonecrosis accounts for variability within and between muscle samples. Regenerative capacity (RI) sharply decreased over an age range associated with significant clinical decline in DMD boys whereas the opposite pattern of a marked increase was observed in DMD canines treated with SAT-3247. Taken together, results demonstrate translatability of RI from preclinical to human muscle and potential to evaluate treatment response in boys of similar age in the BASECAMP (NCT07287189) study of SAT-3247.

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