Abstract Details

To describe two presymptomatic infants diagnosed with spinal muscular atrophy (SMA) through newborn screening who were initially eligible for onasemnogene abeparvovec therapy but experienced temporary contraindications delaying gene therapy initiation and were managed with risdiplam as a bridging treatment.

Onasemnogene abeparvovec, a gene replacement therapy for SMA, is contraindicated in certain clinical situations, including high anti–AAV9 antibody titers and low body weight. Delays in therapy initiation may compromise motor outcomes in rapidly progressive SMA. The use of risdiplam, a survival motor neuron (SMN2) splicing modifier, may serve as an effective bridge therapy until gene therapy becomes feasible.

We retrospectively reviewed the clinical course of two SMA presymptomatic patients under the care of our neuromuscular center. Both were approved for onasemnogene abeparvovec but faced temporary contraindications: one due to elevated anti–AAV9 antibody titers (1:1600) and the other due to body weight below the minimum threshold for dosing. Both received oral risdiplam (0.2 mg/kg/day, titrated to 0.25 mg/kg/day) until contraindications resolved. Clinical, laboratory, and functional outcomes were monitored throughout treatment.

The patient with high anti–AAV9 antibodies showed gradual titer decline to 1:25 after 5 months, allowing successful administration of onasemnogene abeparvovec without complications. The low-weight patient achieved the required body weight after 1 month of nutritional optimization and risdiplam therapy. In both cases, bridging risdiplam treatment was well tolerated and associated with clinical stabilization and mild motor gains (improved CHOP-INTEND scores by 4–6 points). No treatment-emergent adverse events were observed.

Temporary contraindications such as anti–AAV9 seropositivity or low body weight may delay gene therapy initiation in SMA. Bridging treatment with risdiplam can maintain motor function and allow safe transition to gene therapy once contraindications resolve. These cases highlight the importance of individualized therapeutic strategies in optimizing outcomes for infants with SMA.