Maternal-Fetal Administration of Risdiplam Partially Rescues the SMNΔ7 Mouse Model of Spinal Muscular Atrophy

Area of Science:

• Neurology
• Genetics
• Pharmacology

Background:

• Spinal muscular atrophy (SMA) is a genetic disorder caused by SMN1 gene defects, leading to motor neuron degeneration and muscle atrophy.
• Current postnatal therapies improve outcomes but do not offer a complete cure for SMA.
• Investigating prenatal therapeutic strategies is crucial for improving SMA treatment outcomes.

Purpose of the Study:

• To evaluate the efficacy of a prenatal therapeutic strategy for SMA using the SMNΔ7 mouse model.
• To assess the safety and therapeutic effects of prenatal administration of a risdiplam-like compound on dams and SMA mouse pups.

Main Methods:

• A risdiplam-like compound was administered orally to pregnant mice from mid-gestation until birth.
• Maternal reproductive metrics, toxicology, and immune function were assessed.
• Progeny were monitored for phenotype, and pathological hallmarks of SMA, including motor neuron, neuromuscular junction, and muscle health, were investigated.

Main Results:

• Maternal-fetal drug transfer was safe and improved weight, motor function, and survival in SMA mice.
• Prenatal treatment rescued myofiber area and improved presynaptic components and postsynaptic endplate size at the neuromuscular junction.
• Motor neuron pathology was not fully rescued due to the absence of postnatal intervention, highlighting the need for continued therapy.

Conclusions:

• Prenatal administration of a risdiplam-like compound shows therapeutic potential for SMA.
• Optimal treatment outcomes for SMA necessitate a combination of both prenatal and postnatal therapeutic approaches.
• This study isolates the effects of embryonic exposure to the therapeutic agent.