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       AAV Therapy: A Successful One-Patient SPG50 Gene Therapy Trial
        
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       In hereditary spastic paraplegia type 50 (SPG50)—an ultrarare form of
       neurodevelopmental/neurological disorder described as ideal for gene
       therapy—Canadian researchers successfully created and completed a
       phase 1 gene replacement therapy trial for a single patient. They
       presented their results in _Nature Medicine_ , also providing an
       outline that others can follow in future gene therapy studies for rare
       diseases.1
        
       Additionally, these study results have spurred a larger US-based trial
       to treat other patients with SPG50.
        
       SPG50 is a progressive disease marked by developmental delay and
       progressive microcephaly. The patient here was a 4-year-old boy
       diagnosed with SPG50 by whole-exome sequencing at age 18 months.
       Twelve months after intrathetically receiving the adeno-associated
       virus (AAV)-based gene therapy product carrying the _AP4M1_ gene, the
       boy's disease course seemed stabilized, the therapy was well
       tolerated, and he had experienced no serious adverse events.
        
       Hereditary spastic paraplegia type 50 is a progressive disease marked
       by developmental delay and progressive microcephaly | Image Credit:
       vladimircaribb-stock.adobe.com
        
       The authors noted that longer follow-up is, of course, necessary to
       confirm the therapy's safety and to continue to provide insights on
       its efficacy—but their work exemplifies the growing potential to
       develop gene- and/or mutation-specific treatments for many rare
       diseases.2
        
       ##  **The Young Patient**
        
       This boy is only 1 of about 100 patients worldwide, and the only in
       Canada, with SPG50. At the predosing baseline, the authors described,
       he could crawl 5 feet, pull himself up to stand momentarily at a
       table, and walk a few steps with assistance. Nonverbal, and with
       limited communication through gestures and sounds, he had a pincer
       grasp and could feed himself with his hands, stack 2 blocks, and
       scribble. Progressive limb spasticity is a major SPG50 disease
       component, the team wrote, noting that this patient's "physical
       examination was most notable for diffuse spasticity (lower extremity
       more affected than upper extremity) and hyperreflexia."
        
       The study's secondary end point was efficacy, which was met with
       disease stabilization. The authors measured spasticity using 2 scales
       developed for cerebral palsy: the Tardieu and modified Ashworth
       scales. Although not all data assessments could be completed because
       of the young patient's discomfort, there were no negative changes in
       successfully scored joints compared with predosing assessments, said
       the team.
        
       In subjective analysis, the authors saw no overall disease worsening
       or loss of skills. After treatment, the boy could stand with his heels
       on the ground—previously not possible. He also could tolerate longer
       periods of standing in a stander and walking with an assistive device.
       Some developmental and motor domain skills improved, while adaptive
       behavior saw a modest decline according to one scale.
        
       Safety and tolerability, the trial's primary end points, were met as
       well.
        
       ##  **Gene Therapy Approach to SPG50**
        
       Among the reasons thatSPG50 is "an ideal candidate disease" for gene
       therapy, the authors noted, is that "the coding sequence is small
       (1359 base pairs) and fits within a self-complementary AAV vector."
       Because causative mutations result in loss of expression/function,
       gene re-expression would be anticipated to be effective, they
       continued. Plus, because the AP-4 complex is an obligate
       heterotetramer, that may protect against overexpression-related
       toxicity.
        
       The study did not come cheap. As estimated by the CureSPG50
       Foundation—which was founded by the patient's family soon after the
       child was diagnosed, specifically to develop a gene therapy—the total
       cost of the project for preclinical development was Canadian
       $3,500,000. The clinical trial's cost was about $250,000, with more
       expenses related to concomitant medications (tacrolimus and
       sirolimus); there were also difficult-to-estimate in-kind
       contributions.
        
       "Cost-reducing innovations are clearly needed" to develop more gene
       therapies for rare diseases, the authors declared. Worldwide, rare
       diseases affect more than 400 million individuals, but fewer than 5%
       of the diseases have treatments.
        
        **References**
        
       1\. Dowling JJ, Pirovolakis T, Devakandan K,et al.AAV gene therapy for
       hereditary spastic paraplegia type 50: a phase 1 trial in a single
       patient. _Nat Med._ Published online June 28, 2024.
       doi:10.1038/s41591-024-03078-4
        
       2\. Kim J, Woo S, de Gusmao CM, et al. A framework for individualized
       splice-switching oligonucleotide therapy. _Nature._
       2023;619(7971):828-836. doi:10.1038/s41586-023-06277-0
        
        
        
        
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