Targeted genetic therapies for inherited disorders that affect both cardiac and skeletal muscle

Figures

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  FIGURE 1. An overview of cardiomyocyte biology highlighting pathways altered in disease. The sodium/calcium exchanger and sodium/potassium ATPase mediate the entry of ions, depolarising the cell and triggering Ca2+ entry by the voltage‐gated L‐type calcium channels. This instigates calcium‐induced calcium release from the sarcoplasmic reticulum. Cytoplasmic calcium then binds the troponin complex allowing cross‐bridge formation and the ATPase driven myosin power stroke. The ATP used for these processes is supplied by the dense lattice of mitochondria packaged between sarcomeres. Mitochondrial function is supported by frataxin in complexes I–III, α‐glucosidase aids the supply of glucose for ATP production and dystrophin is integral to anchoring myofibrils to the sarcolemma allowing efficient force transduction between cells. Created using BioRender.com.

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  FIGURE 2. Dystrophin, Duchenne muscle dystrophy and therapeutic opportunities. (a) Physiological expression of dystrophin maintains cellular homeostasis and ion exchange by mechanical association of the dystrophin‐associated protein complex (DAPC), which includes the dystroglycan and sarcoglycan complexes, to the mechanical apparatus via cytoskeletal actin. This in turn links to the mitogen‐activated protein kinase (MAPK) and protein kinase A (PKA) pathways and nitric oxide synthase (NOS) signalling, enabling downstream signalling, correct localisation of neuronal NOS (nNOS) and subsequent secretion of vasodilative nitric oxide (NO). (b) Loss of dystrophin disrupts myofibril mechanical linkage to the sarcolemma, causing the DAPC to disassemble causing membrane damage. Loss of dystrophin‐mediated anchoring of cytoskeletal components interrupts PKA and MAPK signalling and causes myofibril disarray. Contractile processes activate Rac1 signalling, resulting in reactive oxygen species (ROS) damage. Loss of NOS signalling results in localised ischaemia due to mislocalisation of nNOS and a subsequent lack of NO secretion in the local vasculature. (c) Current therapeutic approaches include…

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  FIGURE 3. The role of frataxin in healthy and FA cardiomyocyte, highlighting opportunities for therapeutic intervention. (a) Expression of frataxin supports mitochondrial function by mediating iron–sulphur cluster formation, which is a key component of respiratory chain complexes I, II and III, a cofactor to aconitase, essential in the Krebs cycle, and contributes to haem formation and iron storage. (b) Decreased frataxin expression interferes with ATP production by reducing aconitase activity causing the interruption of the respiratory chain complexes I–III. Deregulation in iron metabolism results in iron accumulation, decreased haem production and ROS damage. (c) Therapeutic strategies include antioxidants against ROS damage, re‐purposing of FDA approved drugs that increase frataxin expression, iron chelation to counter iron accumulation, and supplementation with nicotinamide riboside to boost NAD+ and protect against the metabolic vacuum in FA cardiomyopathy. Gene therapy approaches aim to target and cleave the expanded GAA repeat with the aim of increasing FXN expression. Created using Biorender.com.

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  FIGURE 4. The role of acid α‐glucosidase in Pompe disease, and therapeutic strategies. (a) At physiological expression levels acid α‐glucosidase localises in lysosomes and hydrolyses glycogen to glucose for respiration. (b) A deficiency of acid α‐glucosidase in the cell caused by mutations in GAA results in accumulation of lysosomal glycogen and an inability to fuse lysosomes to phagosomes, causing a build‐up of autophagic material, a lack of organelle clearance, metabolic deficiency and loss of sarcomeres. (c) Therapeutic approaches include enzyme replacement therapy to complement the lack of functional acid α‐glucosidase, delivery of chaperones to stabilise the native and delivered acid α‐glucosidase, and viral delivery of wild‐type GAA gene or precursor acid α‐glucosidase. Alternatives include the overexpression of TFE3 and EB to induce secretion of lysosomal contents and RNA interference of glycogen synthase 1 (GS1) and glycogenin (GNN) to limit the production of glycogen. Created using BioRender.com.