Single-patient gene therapy clinical trial at SickKids carves a path for Precision Child Health

TORONTO – A team at The Hospital for Sick Children (SickKids) has delivered an individualized gene therapy in a single-patient clinical trial for four-year-old Michael Pirovolakis, with the aim of treating Michael’s ultra-rare genetic condition, spastic paraplegia type 50 (SPG50).

Michael was one year old in 2019 when he underwent genome-wide sequencing at SickKids, which revealed he had two disease-causing variants in a gene called AP4M1. These variants result in SPG50, a progressive neurodegenerative disorder that causes developmental delays, speech impairment, seizures, a progressive paralysis of all four limbs, and can be fatal. In the years following his diagnosis, Michael experienced persistent developmental delays and progressive, increased muscle spasticity.

At the time of his diagnosis and to this day, Michael is the only known patient with SPG50 in Canada.

It’s believed there are approximately 80 children around the world with SPG50, making the condition an “ultra-rare disease.”

“We often think of rare disease as something that impacts a very small number of patients. In reality, it’s estimated that more than one million Canadians have a rare disease and one in 25 children in Canada will be born with some type of a rare disease,” says Dr. Jim Dowling, Staff Physician in the Division of Neurology and Senior Scientist in the Genetics & Genome Biology program at SickKids, who led Michael’s clinical trial.

Michael’s treatment options were extremely limited and his parents, Georgia and Terry, started the charity, CureSPG50, raising millions of dollars in the hopes of developing a gene therapy that could help Michael and others like him with SPG50. They worked with doctors and companies in the U.S. and Canada to coordinate the research, development and manufacturing of a gene replacement therapy that is meant to provide a normal version of the AP4M1 gene.

“When Michael was diagnosed, we knew we would do anything, go anywhere and give up everything to save him,” says Terry, Michael’s father. “As they say, it takes a village and our village showed up. Thanks to our incredible community of donors and the tireless work of physicians, scientists and researchers across the world, we were able to create a first-ever gene therapy for SPG50.”

Once the therapy had been successfully tested in animal models in the lab and was ready to be given to Michael, a team of SickKids doctors and researchers sprang into action to open a clinical trial. Clinical trials are a crucial part of the drug development pipeline and are often the point at which potential therapeutics will fail.

SickKids had never before conducted a gene therapy clinical trial for only one patient. Dowling led the design of the trial, which was key to ensuring Michael’s safety and the integrity of the data being collected on the therapy. The clinical research team consulted with experts around the world and coordinated multiple teams and services within SickKids to be able to provide such a novel treatment. SickKids received Health Canada approval for the trial, and only three years after Michael’s diagnosis, in March 2022, he received a therapy designed specifically for his unique condition.

“Successfully conducting the trial for Michael was not only a key milestone for him and his family but also for achieving SickKids’ vision for Precision Child Health, a movement to deliver individualized care for every patient,” says Dr. David Malkin, Co-Lead, Precision Child Health, Director of the Cancer Genetics Program and the CIBC Children’s Foundation Chair in Child Health Research at SickKids. “Not only can rare diseases be a springboard to figure out how to treat more common conditions, but learnings from Michael’s trial will help carve out a path for SickKids to explore innovative, precision-based treatment options for other patients with rare, genetic diseases.”

More than three months later, Michael is doing well and there are some indications his symptoms may be improving. He will be monitored over time to see whether the therapy effectively slows the progression of his disease and potentially reverses some of its impacts. CureSPG50 is working with institutions around the world to establish clinical trials for other children with SPG50 and continue testing the new therapy.