The mitochondria-targeting peptide elamipretide potentiates dystrophin expression induced by an exon-skipping morpholino in the mdx mouse model


Pre-Clinical Research

Poster Number: 122


David Brown, PhD, Stealth BioTherapeutics, Ashley Vining, PhD, Agada Biosciences, Alexandra MacKinnon, PhD, AGADA Biosciences Inc., Pia Elustondo, PhD, AGADA Biosciences Inc., Meagan McKenna, PhD, AGADA Biosciences Inc., Kanneboyina Nagaraju, PhD, AGADA Biosciences Inc.

Exon-skipping Phosphorodiamidate Morpholino Oligomers (PMO) remain one of the few approved treatments for patients with Duchenne Muscular Dystrophy (DMD) that have been shown to increase dystrophin expression. Despite the promise of PMOs for treating DMD, limitations in their uptake and efficacy preclude greater dystrophin production. Mitochondria are postulated to modulate PMO efficacy by influencing membrane repair and inflammation; mitochondrial dysfunction is known to be an early event in DMD disease progression. In this study, we sought to determine if the mitochondria-targeting peptide elamipretide (MTP-131) would augment PMO-mediated dystrophin production in an mdx mouse model. Four-week-old C57BL/10ScSn-Dmdmdx/J (mdx) mice were divided into one of four treatment arms: saline, PMO (125 mg/kg, retro-orbital once weekly), elamipretide (5 mg/kg, IP once daily), or combination therapy of weekly PMO and daily elamipretide (same dosing paradigm). At the end of the 7-week study duration, dystrophin expression in the tibialis anterior muscle was quantified via western blot. As expected, dystrophin protein levels were very low in the untreated mdx mouse (0.7% ? 0.4% of healthy BL10 control animals), and elamipretide treatment alone did not alter dystrophin expression. Treatment with the PMO increased dystrophin expression to 3.7% ? 2.1%, P<0.05 versus untreated mdx). Interestingly, combination therapy of PMO and elamipretide more than doubled the mean level of dystrophin protein (7.9% ? 6.0%, P<0.05 versus PMO alone). Immunofluorescence staining with an anti-dystrophin antibody provided corroborating support for the increase in dystrophin expression. Inflammation was significantly higher in the mdx mouse muscle, and elamipretide alone trended to lower markers of inflammation by 34% on average. In vitro specific force production was significantly lower in the EDL muscle from mdx mice, and none of the treatments influenced force generation. These data highlight the potential synergy between a mitochondria-targeting compound and exon-skipping PMOs for the treatment of patients with DMD.