C.O.3 Efficacy of cardiac actin over-expression therapy for ACTA1 disease seems mutation specific

Abstract Around 200 different mutations in the skeletal muscle actin gene ( ACTA1 ) are known to cause myopathies with various pathologies (e.g. actin aggregates, nemaline bodies, intranuclear rods, cores, caps, and zebra bodies). Developing therapeutic approaches targeting specific mutations is therefore daunting. Cardiac actin (ACTC; the major actin isoform in adult heart) is 99% identical to ACTA1 protein, and plays an important role in fetal skeletal muscle. Thus we hypothesized ACTC might effectively substitute for ACTA1 in postnatal skeletal muscle. Confirming this, we previously showed that the early lethality of a recessive ACTA1 disease model ( Acta1 knock-out mice) could be rescued by transgenic ACTC over-expression in post-natal skeletal muscles. Experimental and anecdotal evidence indicates that dominant ACTA1 disease is modulated by the relative amount of mutant ACTA1 protein. We thus investigated harnessing over-expression of ACTC in an attempt to decrease the proportion of mutant ACTA1 in the total striated actin pool, as a candidate therapy. We bred ACTC over-expressing mice with a severe mouse model of dominant ACTA1 disease ( ACTA1 (D286G). Acta1 +/−). Usually ∼67% of mice in this line present with paralysis of the hind limbs, dying before 30 days of age, whilst only ∼11% showed the same phenotype when also expressing ACTC. Thus ACTC over-expression produces a significant amelioration of this disease phenotype. We also bred ACTC over-expressing mice with the dominant Acta1 (H40Y) mouse model. Male mice in this line exhibit a decreased lifespan, with ∼50% dying by 9 weeks of age, and a further 30% dying by 5 months of age. Transgenic over-expression of ACTC did not significantly alter their mortality rate. These data indicate that in addition to being effective for recessive ACTA1 mutations, cardiac actin over-expression might be therapeutic for some dominant ACTA1 mutations, but not others.