Safety and Efficacy of <scp>DTX401</scp> , an <scp>AAV8</scp> ‐Mediated Liver‐Directed Gene Therapy, in Adults With Glycogen Storage Disease Type I a ( <scp>GSDIa</scp> )

Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening, inherited carbohydrate metabolism disorder caused by glucose-6-phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno-associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open-label, phase 1/2, dose-escalation, 52-week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × 10¹² genome copies (GC)/kg, and three participants each in Cohorts 2, 3, and 4 received 6.0 × 10¹² GC/kg. Corticosteroids were administered to mitigate vector‑induced inflammatory response. All participants experienced a treatment-emergent adverse event (TEAE) and a related TEAE. No participant experienced a dose-limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%). Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); p < 0.001. DTX401 showed a favorable safety and efficacy profile at Week 52. Participants in all cohorts showed significant cornstarch need reductions from baseline to Week 52.