The FDA approved Ultragenyx’s gene therapy Fayuvi (rebisufligene etisparvovec) for Sanfilippo syndrome type A, making it the first FDA-approved treatment specifically for the ultra-rare, fatal lysosomal storage disorder. The decision follows a prior complete response letter tied to manufacturing issues. Fayuvi is delivered as a one-time intravenous infusion using an AAV9 vector designed to deliver a functional copy of the SGSH gene and enable production of the missing sulfamidase enzyme. In an open-label, single-arm pediatric study, patients maintained or improved cognitive function compared with historical controls, with particularly notable benefits in younger or earlier-stage patients. Regulatory designations included orphan drug, fast track and breakthrough therapy. The therapy’s label includes warnings for thrombotic microangiopathy and potential tumor risks associated with gene therapy integration, and the regimen requires corticosteroids beginning before infusion and continuing for eight weeks. The approval meaningfully shifts the treatment landscape from symptom-focused care to a disease-modifying approach for MPS IIIA patients, underscoring the FDA’s willingness to use accelerated pathways in small, high-need populations.