i.c.v. delivery of AAV9-synapsin-promoted caveolin-1 attenuates neuromuscular deficits and neuromuscular degeneration in hSOD1G93A mice.

Practical and broad biodistributable gene delivery interventions are essential for advancing therapeutic strategies targeting neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously demonstrated that subpial delivery of AAV9-synapsin-promoted caveolin-1 (SynCav1) afforded significant neuroprotective effects in mutant superoxide dismutase (SOD)-1-induced ALS pathology. However, subpial delivery is regionally restricted, technically challenging, and highly invasive. This study evaluated whether the intracerebroventricular (i.c.v.) route of administration (ROA), an alternative CNS delivery strategy less invasive than direct spinal cord injections, could achieve broader CNS biodistribution and produce functional or histological benefits in hSOD1G93A mice. i.c.v. administration of AAV9-SynCav1 achieved widespread Cav-1 overexpression in the motor cortex and spinal cord. SynCav1-treated male mice exhibited improved running wheel (RW) performance and better motor-evoked potentials. Immunofluorescence revealed attenuated degeneration of cholinergic motor neurons (MNs) in the cervical and lumbar ventral horn, as well as preserved diaphragm neuromuscular junction (NMJ) innervation in SynCav1-treated mice. These findings serve as preclinical proof of concept that i.c.v. delivery of AAV9-SynCav1 can achieve CNS target engagement and produce selective functional and anatomical benefits in hSOD1G93A mice.