DMD – ANIMAL MODELS & PRECLINICAL TREATMENT: P.209 Repeated administration of cardiosphere-derived cells preserves exercise capacity and muscle function for at least one year in mdx mice

Abstract

Cardiosphere-derived cells (CDCs) are cardiac progenitor/stromal cells with immunomodulatory, anti-fibrotic, and pro-regenerative properties. These therapeutic actions antagonize crucial pathways central to the pathology of Duchenne muscular dystrophy (DMD). We have previously demonstrated that CDCs are therapeutic in Duchenne muscular dystrophy (DMD) patients and in mdx mice. Our earlier preclinical work centered on the infusion of a single dose of CDCs to aged mdx mice. Due to the progressive nature of DMD, we questioned whether repeated CDC infusion to mdx mice, beginning in youth, could prevent disease progression into adulthood. Therefore, we intravenously infused CDCs monthly into 8-week-old mdx mice during a 12-month study period. Maximal exercise capacity was measured at baseline and bimonthly thereafter, and skeletal muscle function of the solei and diaphragm was measured in subsets of mice euthanized quarterly. CDCs preserved maximal exercise capacity during the entire study duration. In contrast, maximal exercise capacity in vehicle-infused mdx mice declined with age. Further, muscle function of the solei was also maintained with CDCs – in contrast to vehicle. CDCs also improved diaphragm muscle function relative to vehicle. However, force-producing capacity declined in both groups with age. Histology showed CDCs dramatically improved dystrophic features of the diaphragm and reduced fibrosis as early as 3 months following treatment, which remained evident after 12 months of treatment. The deterioration in mdx mouse physiology resulting from natural aging is consistent with DMD. To date, CDCs have been administered to DMD patients only in advanced stages of the illness. The present finding, that early and repeated CDC treatments delay disease progression, motivate reconsideration of this paradigm.