Anti-Sense Oligonucleotide as a Therapeutic for Synucleinopathies: Pharmacokinetic, Safety and Efficacy Evaluation

Effective blood-brain barrier (BBB) penetration is a significant challenge for antisense oligonucleotide (ASO) therapies targeting neurodegenerative diseases. We utilized a peptide (ApoB11) mediated transport delivery of an ASO to the CNS following systemic delivery to reduce expression of targeted transcripts for neurodegenerative diseases. This study evaluates the pharmacokinetics, CNS penetration, and therapeutic efficacy of ApoB11:2'-OMe ASO-α-Syn, an ASO for α-synuclein (α-Syn) suppression in synucleinopathies. After a single intraperitoneal (IP) injection (2 mg/kg) in C57BL/6 mice, ApoB11:ASO-α-Syn showed robust brain penetration, reaching peak concentrations (Cmax = 0.14 nMol/mg) at 1.5 hours and an extended brain half-life (t1/2 = 646.2 hours), indicating prolonged CNS retention. Immunofluorescence confirmed widespread uptake in neurons and endothelial cells. The ASO also accumulated in the liver (Cmax = 419.5 nMol/mg, t1/2 = 104.9 hours), consistent with receptor-mediated uptake. Acute and subacute toxicity studies revealed no systemic toxicity at the highest non-lethal dose (32 mg/kg). In a mouse model of dementia with lewy body (DLB) mice overexpressing human α-Syn, ApoB11:ASO-α-Syn reduced α-Syn mRNA and protein levels in the hippocampus and cortex by ~50% at 16 mg/kg. These results demonstrate that ApoB11 is an effective ASO carrier for CNS delivery, supporting its potential as a therapeutic strategy for synucleinopathies.