Re-Purposing Sapropterin (Kuvan) for ACTA2-Related Multisystemic Smooth Muscle Dysfunction Syndrome: A Translational Mechanistic and First-In-Human Therapeutic Report.
An existing drug repurposed for an ultra-rare fatal childhood disease stabilized brain blood vessels and improved symptoms in the first treated patient, suggesting a disease-modifying approach.
For the ultra-rare and lethal ACTA2-related multisystemic smooth muscle dysfunction syndrome, in silico drug screening identified sapropterin dihydrochloride as a candidate to restore disrupted actin polymerization caused by the p.R179H mutation, with validation in patient-derived fibroblasts showing improved actin organization. First-in-human off-label treatment of a pediatric patient with ACTA2-MSMDS resulted in cerebrovascular stabilization and clinical improvement on longitudinal follow-up, providing n-of-1 translational proof-of-concept for sapropterin as a disease-modifying candidate.
What the study was
- Study design
- first_in_human_n_of_1_translational
- Population
- Single pediatric patient with ACTA2-MSMDS; patient-derived fibroblast cultures
- Sample size
- 1
- Category
- Drug Development
- Maturity
- Exploratory
- Journal
- Ann Clin Transl Neurol
Why it surfaced
First-in-human translational report for drug repurposing in an ultra-rare, life-threatening vasculopathy with no approved treatments; the mechanistically rigorous pipeline (in silico to fibroblast to patient) with observed clinical benefit provides immediate proof-of-concept for further clinical development in ACTA2-MSMDS.
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