Background: Spinal Muscular Atrophy (SMA) remains a critical clinical challenge despite recent therapeutic advances. Current treatments are limited by suboptimal systemic delivery, inadequate targeting of motor neurons, incomplete rescue of multi-system pathology, and adverse effects. This study investigates DG9-PMO, a novel therapeutic approach, combining an antisense oligonucleotide (ASO), termed as Phosphorodiamidate Morpholino Oligomer (PMO), with a novel cell penetrating peptide, DG9. DG9 derived from a naturally expressing T-cell peptide in humans enhances cellular uptake of PMO, potentially eliminating the need for invasive intrathecal injections.
Objective and Methods: The study aimed to characterize the mechanism of DG9-mediated PMO uptake and assess its therapeutic efficacy in SMA mouse models. Mice were administered DG9-PMO on postnatal days 0, 2, 28, and 56. The phenotypic rescue was compared against non-treated (NT) controls, limited-dosing groups, and treatment with 2′-O-methoxyethyl (MOE), another ASO chemistry. Key assessments included survival rates, SMN protein restoration, muscle pathology, vasculopathy, cardiac and hepatic function, and respiratory performance.
Results: DG9-PMO administration extended mean survival to over 200 days compared to 8 days in NT mice. Unlike limited-dosing group, continuous administration effectively rescued vasculopathy, preventing distal necrosis beyond postnatal day 160, and treatment achieved comprehensive phenotypic rescue, including increased body weight, improved motor function, and enhanced muscle strength. Sustained SMN protein levels were observed in central and peripheral tissues, correlating with long-term improvements in multiple organs. Cardiac function, assessed via echocardiography, significantly surpassed outcomes with MOE treatment. Furthermore, respiratory dysfunction, a critical issue in SMA, was ameliorated, alongside marked reductions in hepatic damage and muscle pathology. In the central nervous system, apoptosis and motor neuron loss were substantially mitigated. Importantly, no toxicity was detected, even after multiple administrations, underscoring the safety of this platform.
Conclusion: These findings highlight the potential of DG9-PMO to address critical limitations of existing treatments and enhance clinical outcomes for SMA patients.