Recombinant SMN protein synergizes with spinal muscular atrophy therapy to counteract pathological motor neuron phenotypes

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by loss of the SMN1 gene and insufficient levels of survival motor neuron (SMN) protein. Although SMN2-targeting therapies have transformed SMA treatment, their efficacy is limited by delayed SMN induction, restricted SMN2 transcript availability, and heterogeneous patient responses. Here, we developed a recombinant full-length human SMN protein fused to the HIV-1 TAT protein transduction domain (TAT-flSMN) as a rapidly deliverable, “ready-to-use” SMN replacement strategy. Biophysical analyses demonstrated that TAT-flSMN is correctly folded, oligomerizes similarly to native SMN, and efficiently enters motor neuron-like cells. In SMA cellular models, TAT-flSMN restored neurite outgrowth and reduced apoptotic cell death in a dose-dependent manner. Importantly, in SMA patient-derived iPSC motor neurons, TAT-flSMN significantly improved neuronal morphology and survival, and displayed synergistic effects when combined with an SMN2 splicing-modifying antisense oligonucleotide. These findings provide proof-of-principle that direct SMN protein delivery can rapidly boost intracellular SMN levels and enhance the efficacy of existing therapies, supporting TAT-flSMN as a promising adjunct strategy for SMA treatment.