New avenue for treating myopathy

West Australian Institute of Medical Research (WAIMR) scientists have rewritten the book on nemaline myopathy, a type of congenital myopathy that can cause death or paralysis in newborn babies.

Previously it was thought if mutant actin protein was apparent in patients with myopathy their muscles could never work, but this new research proves reducing the amount of mutant actin protein can radically alter the severity of the disease.

WAIMR research associate Dr Gina Ravenscroft says, "If we could reduce the amount of mutant actin we could help alleviate the disease in patients".

Patients with nemaline myopathy have a mutation in the ACTA1 gene that 'encoats' the actin protein—one of proteins that make skeletal muscles contract. Mutations in the gene will not allow the muscles to contract, resulting in paralysis.

"Children often die within the first year of life because the diaphragm and the muscles of the ribcage contain the mutant protein; so the children die from respiratory failure," Dr Ravenscroft says.

To show that reducing the amount of mutant actin can alleviate the disease, WAIMR researchers inserted a copy of the mutant gene in mouse models and experimented with different mutant loads.

According to Dr Ravenscroft, some mice with 25 per cent actin were indistinguishable from normal mice.

"But if the load was increased to 45 per cent the mice had trouble moving, indicating paralysis," she says.

"However, some of the mice with 35 per cent looked normal too, so we think there is a critical region between 35-45 per cent.

"That small difference can have a huge impact on quality of life."

The concept was proven by breeding transgenic mice with the ACTA1(D286G) mutation, meaning the team crossed different mice lines to change the load of the mutant actin.

The next step is to find the treatment.

"So we'll need to perform many drugs screens to find a compound that may work to alter the levels of normal to mutant actin," Dr Ravenscroft says.

The team is also proposing to investigate viral delivery of either heart or skeletal muscle actin as treatments after demonstrating that replacing the defective actin with heart actin could save mouse models, which would have normally died within nine days of birth.

"Viral therapy has been trialled for dystrophies using adeno-associated viruses and they look quite promising, so the next phase is to treat the mice using viruses."

The paper, 'Mouse models of dominant ACTA1 disease recapitulate human disease and provide insight into therapies,' was published in prestigious journal Brain.

Dr Ravenscroft will present the findings to the World Muscle Society in October.

(Source: Science Network Western Australia: Brain)