Cardiac  -actin over-expression therapy in dominant ACTA1 disease

Abstract

More than 200 mutations in the skeletal muscle α-actin gene (ACTA1) cause either dominant or recessive skeletal muscle disease. Currently, there are no specific therapies. Cardiac α-actin is 99% identical to skeletal muscle α-actin and the predominant actin isoform in fetal muscle. We previously showed cardiac α-actin can substitute for skeletal muscle α-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease. Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein. Experimental and anecdotal evidence nevertheless indicates that the severity of dominant ACTA1 disease is modulated by the relative amount of mutant skeletal muscle α-actin protein present. Thus, we investigated whether transgenic over-expression of cardiac α-actin in postnatal skeletal muscle could ameliorate the phenotype of mouse models of severe dominant ACTA1 disease. In one model, lethality of ACTA1(D286G). Acta1(+/-) mice was reduced from ∼59% before 30 days of age to ∼12%. In the other model, Acta1(H40Y), in which ∼80% of male mice die by 5 months of age, the cardiac α-actin transgene did not significantly improve survival. Hence cardiac α-actin over-expression is likely to be therapeutic for at least some dominant ACTA1 mutations. The reason cardiac α-actin was not effective in the Acta1(H40Y) mice is uncertain. We showed that the Acta1(H40Y) mice had endogenously elevated levels of cardiac α-actin in skeletal muscles, a finding not reported in dominant ACTA1 patients.

Rational design of a compact CRISPR-Cas9 activator for AAV-mediated delivery

“…Examples of such disorders include Nemaline Myopathy, Sickle Cell Disease, as well as Spinal Muscular Atrophy. [29][30][31] Many of these highlighted disorders are due to mutations that affect cellular function in difficult to reach, or large areas of tissue, that will be difficult to deliver a virus to. In such cases, where neurological tissue, or expansive, difficult to reach tissue must be studied or treated, a dual vector AAV system may be unnecessarily cumbersome to administer in a broad range of experimental and clinical settings as opposed to a single vector virus.…”

Current and future therapeutic approaches to the congenital myopathies

“…These findings have prompted investigation of cardiac ␣-actin upregulation as a possible therapeutic avenue in various mouse models of ACTA1-related NM. In one transgenic line carrying the D286G mutation, muscle weakness and lethality were significantly reduced whilst in another model expressing H40Y, the up-regulation of ACTC did not have any noticeable positive or beneficial effect [120]. The mechanisms underlying such discrepancies remain to be determined.…”

Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction

“…Down-or upregulation of genes acting in related pathways may become particular relevant for different forms of CNM: Recent studies demonstrate that dynamin 2 downregulation 195 , or targeting of class II and III PI3 kinases in muscle 196 can rescue the phenotype in XLMTM animal models, suggesting pharmacological modification of intricately linked pathways a potential treatment modality for XLMTM and, possibly, other forms of CNM. Upregulation of cardiac actin may be a therapeutic approach for patients with ACTA1 null mutations 197,198 . Pharmacological therapies potentially applicable to the CMs can be grossly divided into 3 principal approaches: i) direct modification of altered protein function (for example modification of RyR1 release in RYR1-related myopathies) or ii) enhancement of thin-thick filament interactions (for example, in some NMs), and iii) those aimed at non-specifically ameliorating downstream effects of the specific gene mutation.…”