Intravenous administration of a PHP.eB vector overexpressing neuronal Caveolin-1 delays motor neuron and neuromuscular degeneration in a TDP-43 mouse model of ALS.

TDP-43 proteinopathy is observed in over 95% of ALS cases, yet effective disease-modifying therapies remain elusive. We previously showed that neuron-specific overexpression of caveolin-1 via SynCav1 extended survival and delayed neurodegeneration in an SOD1 mouse model of ALS. Here, we further assessed the effect of systemic delivery of AAV-PHP.eB-SynCav1 in TDP-43A315T mice. At 24 weeks, SynCav1-treated mice showed preserved motor neuron (MN) morphology, maintained neuromuscular junction (NMJ) innervation, and normalized pathologically driven neurotrophic transcription in the spinal cord. Immunoblotting revealed that SynCav1 increased calcium-impermeable GluA2 in membrane lipid rafts of lumbar SC. However, these effects diminished with disease progression: by 32 weeks, lumbar MN loss and NMJ denervation were no longer significantly different between TDP-43-SynNull and TDP-43-SynCav1 mice, although partial protection was observed in the cervical spinal cord. These findings establish SynCav1 as an effective early-phase neuroprotective strategy and highlight the need for combinatorial approaches to achieve sustained protection.