Michael Pirovolakis was diagnosed with spastic paraplegia type 50 (SPG50) when he was 18 months old. SPG50 is an “ultra-rare” progressive neurodegenerative disorder that causes developmental delays, speech impairment, seizures, a progressive paralysis of all four limbs, and is typically fatal by adulthood. Approximately 80 children around the world are affected by this genetic condition and Pirovolakis was the only person with SPG50 in Canada, at the time of his diagnosis. Shortly after diagnosis, the family created the CureSPG50 Foundation with the goal of developing SPG50 gene therapy.

In March 2022—less than three years after his initial diagnosis—Pirovolakis received an AAV-based gene therapy. He is the only patient in a clinical trial being run at the Hospital for Sick Children (SickKids), affiliated with the University of Toronto.

Now, findings from the clinical trial (NCT06069687) are published in Nature Medicine in the paper, “AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.” The authors report that, after treatment, the course of Pirovolakis’ condition was altered significantly. In addition, they present a road map for individualized treatment of an ultra-rare disease.

“When we heard that Michael had been diagnosed with this terrible disease, our world fell apart. We were lost and broken as a family,” said Pirovolakis’ parents, Terry and Georgia. “Thankfully, we had an amazing team at SickKids and a supportive community that lifted us up and gave us the confidence to raise millions of dollars and create a therapy, not only for Michael, but for other children affected by this disease for generations to come.”

In Pirovolakis’ case, SPG50 is caused by biallelic pathogenic variants in the AP4M1 gene, encoding a subunit of the adaptor protein complex 4 (AP-4). SPG50, the authors noted, is “an ideal candidate disease for gene therapy. The coding sequence is small (1,359 base pairs) and fits within a self-complementary adeno-associated virus (scAAV) vector.”

Led by Jim Dowling, MD, PhD, staff clinician in the division of neurology and senior scientist in the genetics and genome biology program at SickKids, the clinical research team delivered the healthy AP4M1 gene into Michael’s spinal fluid. More specifically, AAV9-AP4M1 was administered at 1 × 1015 vector genomes through intrathecal delivery. This is, the authors noted, “among the largest doses of AAV9-based gene therapy ever administered into the cerebrospinal fluid.”

In the trial, the primary endpoints were safety and tolerability, and the secondary endpoints evaluated efficacy. In the 12 months after he received the treatment, Pirovolakis experienced no serious side effects and, contrary to the hallmark of neurodegenerative conditions like SPG50, his condition does not seem to be progressing further. Preliminary efficacy measures suggest a stabilization of the disease course.

He also began to show potential signs of improvement. For the first time, Pirovolakis was able to stand with his heels on the ground. He also experienced improvements in some aspects of his neurodevelopment.

The clinical research team continues to follow Pirovolakis’ progress, but the trial provides important initial evidence of the safety and efficacy of gene therapy to reduce or halt the progression of SPG50.

“While these ultra-rare diseases are unique, our workflow provides a road map for gene therapies that could help many of the thousands of children in Canada with rare genetic conditions,” said Dowling.

Importantly, the results also highlight how gene therapy can be developed quickly and personalized for individual patients with rare genetic conditions. They hope that this approach can be used for other conditions in the future to help achieve Precision Child Health, a movement at SickKids to deliver individualized care for every patient.

“There are over 10,000 individual rare diseases and most are without therapy,” said Dowling. “We are providing a blueprint that, with adequate funding and support, has the potential to change the lives of patients with rare diseases and a future where every child can benefit from precision medicine.”

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