Silencing of the Ca Channel ORAI1 Improves the Multi-Systemic Phenotype of Tubular Aggregate Myopathy (TAM) and Stormorken Syndrome (STRMK) in Mice.

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) form a clinical continuum associating progressive muscle weakness with additional multi-systemic anomalies of the bones, skin, spleen, and platelets. TAM/STRMK arises from excessive extracellular Ca entry due to gain-of-function mutations in the Ca sensor STIM1 or the Ca channel ORAI1. Currently, no treatment is available. Here we assessed the therapeutic potential of ORAI1 downregulation to anticipate and reverse disease development in a faithful mouse model carrying the most common TAM/STRMK mutation and recapitulating the main signs of the human disorder. To this aim, we crossed mice with mice expressing 50% of ORAI1. Systematic phenotyping of the offspring revealed that the mice were born with a normalized ratio and showed improved postnatal growth, bone architecture, and partly ameliorated muscle function and structure compared with their littermates. We also produced AAV particles containing -specific shRNAs, and intramuscular injections of mice improved the skeletal muscle contraction and relaxation properties, while muscle histology remained unchanged. Altogether, we provide the proof-of-concept that silencing partially prevents the development of the multi-systemic TAM/STRMK phenotype in mice, and we also established an approach to target expression in postnatal tissues.