Objective: To develop a gene therapy treatment for Mucopolysaccharidosis IIIB (MPS-IIIB) based on intravenous administration of ABO-101. Background: MPS-IIIB is a lysosomal storage disorder manifesting early in childhood with severe neurodegeneration. Design/Methods: Transpher B is Phase 1/2 clinical trial assessing the safety and efficacy of a single intravenous administration of ABO-101, a single-stranded AAV9-based vector expressing the human NAGLU gene for the treatment of MPS-IIIB. Primary endpoints are safety and neurocognitive development and secondary endpoints include, among others, evaluation of biomarkers and liver volume. Results: Six patients have been enrolled across two dose cohorts (Cohort 1, 2x1013 vg/kg, n=2; Cohort 2, 5x1013 vg/kg, n=4) with a mean follow-up of 15 months in Cohort 1 (range 9–22 months) and 3 months in Cohort 2 (range 0.5–5 months). Intravenous administration of ABO-101 was well tolerated with no serious drug-related adverse events. Cohort 1 subjects showed a rapid decrease in CSF heparan sulfate fragments at Day30 (n=2, 53%), which decreased further at Months 6 and 12 (n=1, 60% and 70% respectively), as well as significant reductions in urine HS and glycosaminoglycans by Day 90 (Cohort 1: 33.3% and 56.8% respectively n=2, Cohort 2: 64.3% and.83.3% respectively n=1). These reductions were sustained to Month 18 in the patient followed longer (63.3% and 53.9% respectively, n=1). Liver volume excess decreased 33% by Day 30 (Cohort 1, n=2) and 73.6% and 69.8% by Months 6 and 12, respectively (Cohort 1, n=1). Plasma enzyme activity was normalized in patients from Cohort 1 to Day 60–90 and returned to baseline levels by Month 6 (n=2) while remaining normal in Cohort 2 patients by Day 60–90 (n=2). Conclusions: Overall, these data show a good safety and tolerability profile of ABO-101 administered intravenously to children with MPS-IIIB and provide proof of biological activity in several tissues including liver and CNS. Disclosure: Dr. McBride has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Homology Medicine. Dr. McBride has received research support from Abeona Therapeutics, Biomarin, and Shire. Dr. Smith has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis. Dr. Smith has received research support from Abeona Therapeutics. Dr. Couce has received research support from Abeona Therapeutics. Dr. Flanigan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with 4D Molecular Therapeutics, Audentes, and Dynacure. Dr. Flanigan has received research support from Abeona, PTC Therapeutics, Sarepta Therapeutics, and Audentes Therapeutics. Dr. Truxal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abeona Therapeutics. Dr. Truxal has received research support from Abeona Therapeutics. Dr. Simmons has nothing to disclose. Dr. de Castro has received research support from Abeona Therapeutics. Dr. Rinaldi has nothing to disclose. Dr. Oreiro has nothing to disclose. Dr. Jaensch has nothing to disclose. Dr. Fuller has received research support from Abeona Therapeutics. Dr. Ruiz has nothing to disclose.