Background: Onasemnogene abeparvovec-brve (OA-brve) was FDA-approved in November 2025 as an intrathecal (IT) adeno-associated-virus (AAV9)–mediated gene-replacement therapy in spinal muscular atrophy (SMA) patients ≥2 years of age. Approval was based on proven safety, efficacy, and tolerability of OA-brve in the global phase III STEER study that included non-independently ambulant SMA patients between 2 and <18 years of age. Objectives: STREAM is a US multicenter, single-arm, pragmatic study to address critical evidence needs in the treatment landscape for patients ≥ 2 years of age with SMA with focus on the on-label population of OA-brve. Methods: STREAM aims to enroll 36 patients. Consented patients will be enrolled in 3 predefined treatment cohorts: 1) independently ambulatory patients ages 2 to < 18, 2) independently ambulatory patients ages ≥18 years), and 3) non-independently ambulatory patients who are ≥18 years and have a ≥1 baseline entry level of the revised upper limb module (RULM). Each patient will receive the single dose of OA-brve: 1.2 × 10¹⁴ vector genomes delivered in a 3-mL bolus via lumbar puncture. The study will be conducted with a post-treatment follow-up of biannual in-clinic visits for 24 months followed by remote annual visits up to 3 years. The study will measure and characterize longitudinal motor-function trajectories utilizing the Hammersmith Functional Motor Scale (HFMSE) and/or RULM through 24 months; evaluate adverse events (AEs), serious AEs, and clinical laboratory assessments during safety monitoring; characterize longitudinal trajectories of patient-reported outcomes through 24 months, 3 years via annual remote follow-up, and describe healthcare-resource utilization and supportive-care needs to contextualize the therapy’s impact on real-world clinical management. Conclusions: Evidence generated in this study will bridge the gap between a broader US label and earlier trial populations, support clinician decision-making, inform payer evaluations of economic value, and generate long-term data on patients treated with OA-brve.