Spastic hereditary paraplegia type 50 (SPG50) is a typical ultra-rare disease (incidence is less than 1 in 50,000). The disease is caused by biallelic pathogenic variants in the AP4M1 gene, which encodes a subunit of the AP-4 protein complex. It is a progressive neurodegenerative disease. Patients usually begin to show symptoms in infancy, resulting in developmental delay, speech disorders, epileptic seizures, and gradual paralysis of the limbs. In their teens, most patients are wheelchair-dependent and show severe cognitive impairment, usually dying in adulthood.
In fact, SPG50 is an ideal candidate for gene therapy because the coding sequence of its pathogenic gene is small (only 1359bp) and it is a loss-of-function mutation, which is suitable for treatment using adeno-associated viral vector (AAV) delivery. In addition, the progression of the disease lasts for several years, so there is a relatively large treatment window, and patients may have functional benefits before irreversible disability occurs. However, due to the rarity of the disease, only about 80 children have been confirmed to have the disease worldwide, which has hindered the development of gene therapy.
Recently, researchers from the Hospital for Sick Children in Canada, Boston Children's Hospital and the University of Texas Southwestern Medical Center published a paper titled "AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient" in the journal Nature Medicine.
Michael Pirovolakis is a little boy diagnosed with hereditary spastic paraplegia type 50 (SPG50). He was diagnosed with AP4M1 gene mutation (AP4M1 c.916C>T) by whole exome sequencing at the age of 18 months, mainly manifested by developmental delay (inability to stand or walk independently, inability to speak) and microcephaly. He was the only SPG50 patient in Canada at the time of diagnosis. Shortly after the diagnosis, his family established the CureSPG50 Foundation with the goal of developing SPG50 gene therapy.
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Dr. Jim Dowling of the Hospital for Sick Children in Canada led the clinical trial and coordinated the research, development and manufacturing of gene therapy through a multi-center collaboration with doctors and companies in the United States and Canada. The team was able to perform gene therapy on Michael less than 3 years after his diagnosis. In March 2022, Michael received a personalized gene therapy tailored for him in a single-patient clinical trial at the Hospital for Sick Children in Canada, and his condition improved significantly.
Figure 1. Development and implementation of individual gene therapy for SPG50. (Dowling J J, et al. 2024)
In this clinical trial involving only one patient, the research team led by Dr. Jim Dowling used a gene therapy based on adeno-associated virus type 9 (AAV9). Through spinal injection, the correct AP4M1 gene was transferred into the body and entered the nerve cells.
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Dr. Jim Dowling said that although these extremely rare diseases are unique, their workflow provides a roadmap for gene therapy that can help thousands of children with rare genetic diseases.
The team's groundbreaking clinical trial published in the journal Nature Medicine records Michael's journey 12 months after receiving gene therapy and the impact of this clinical trial on the future of genetic medicine in Canada.
In the 12 months since receiving AAV gene therapy, Michael has no serious side effects and, contrary to the characteristics of neurodegenerative diseases such as SPG50, his condition does not seem to progress further. He has also begun to show potential signs of improvement - he is able to stand for the first time and his neurodevelopment has improved in some aspects.
Michael's parents said, "When we heard Michael was diagnosed with this terrible disease, our world collapsed, and as a family, we were lost and broken. Fortunately, we have an amazing team and a supportive community at SickKids Hospital, who inspired us and gave us the confidence to raise millions of dollars and create a therapy, not only for Michael, but also for other children affected by this disease."
The clinical research team continues to follow Michael's progress, and the trial provides important preliminary evidence for the safety and efficacy of using gene therapy to reduce or stop SPG50 disease progression. Importantly, these results also highlight how gene therapy can be developed rapidly and provide personalized treatment for individual patients with rare genetic diseases.
Reference
Dowling J J, et al. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nature Medicine, 2024: 1-6.