In the first study of its kind, a team of scientists at Children’s Medical Research Institute are a step closer to developing a more universal gene therapy that can be used in all patients impacted by the devastating condition, spinal muscular atrophy (SMA).

The work by lead author Dr Grant Logan and senior author Professor Ian Alexander was published in Molecular Therapy.

SMA is an inherited neuromuscular disorder and a leading genetic cause of infant death in Australia. Children who are born seemingly perfectly healthy never gain the ability to crawl, walk, sit up and eventually even lose their ability to breathe, with the most severe cases dying within the first two years of life.

However, gene therapy has proven to be a game changer for infants with SMA – the earliest treated patients are now reaching their seventh birthdays. NSW was the first state in Australia to start a gene therapy program for SMA, with more than 40 newborns having been successfully treated for this life-threatening condition since 2019.

Gene therapy is a revolutionary approach to treating serious genetic diseases, by delivering a healthy copy of a gene to diseased cells to replace or repair a faulty gene. The most efficient delivery systems are those based on viruses and the current SMA gene therapy uses a harmless virus named AAV, which naturally infects humans.

Unfortunately, a small number of infants with SMA are unable to receive the gene therapy because their body has already developed immunity to the AAV vector as a consequence of exposure to the naturally occurring AAV virus circulating in the community.

“Children who have antibodies to AAV (i.e., pre-existing immunity) cannot currently receive the SMA gene therapy because the treatment will be neutralised by their antibodies,’’ Dr Logan said. “We are seeking to solve this problem so that all patients can access this life-saving technology.’’

Dr Logan and his team have been studying the immune response to the AAV vector in patients (children diagnosed with SMA at birth) who were treated and have benefited from the gene therapy.

Dr Logan said, “We find that treated patients make a huge antibody response to the AAV delivery system and this has given us insights into the complexity of the human response to the AAV gene therapy. Additionally, we have isolated a large panel of these antibodies, which will serve as critical and valuable tools to re-engineer the surface of the AAV delivery system to escape the antibodies that already exist in some patients.”

This work could also benefit other children who could be treated using AAV gene therapy for genetic disorders such as Sanfilippo syndrome and Duchenne’s Muscular Dystrophy.

“Completion of this study is like reaching base camp in our quest to develop better AAV delivery systems to get around the problem of pre-existing AAV immunity. We still have a way to go but it is very satisfying to reach this point in the journey and it would be incredible to see this become reality.”

Dr Logan and Professor Alexander worked with colleagues in the Gene Therapy Research Unit at CMRI on this project, as well as scientists from the University of Florida, the University of NSW, Westmead Institute for Medical Research and Sydney Children’s Hospitals Network.

Read full Molecular Therapy publication here.