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

OBJECTIVE

Spinal muscular atrophy (SMA) is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene and subsequent reduction in the expression of survival motor neuron (SMN) protein. The disease is characterized by degeneration of α motor neurons and subsequent muscle atrophy. Postnatal disease modifying therapies improve outcomes yet fall short of a cure. We have investigated a prenatal therapeutic strategy using the SMNΔ7 mouse model of SMA.

METHODS

A risdiplam-like compound was administrated by oral gavage to pregnant mice with treatment initiated mid-gestation and halted on day of birth. Reproductive metrics, liver toxicology, and immune function were assessed in the pregnant dams during gestation and post-birth. Progeny were monitored phenotypically, and pathological hallmarks of SMA were investigated including, but not limited to motor neuron, neuromuscular junction, and muscle health.

RESULTS

Maternal-fetal drug transfer was safe for the pregnant dam and substantially increased weight, motor function, and survival of severe SMA mice. It also rescued and maintained myofiber area. Presynaptic components of the neuromuscular junction were marginally improved in SMNΔ7 pups, whereas postsynaptic endplate size was increased following prenatal risdiplam treatment. Motor neuron pathology was not fully rescued by prenatal exposure to SMN protein, likely because of the lack of continued postnatal intervention. By restricting risdiplam treatment to the prenatal period, we have isolated and assessed therapeutic effects attributable solely to embryo exposure of the therapeutic.

INTERPRETATION: Our efforts demonstrate a combination of prenatal and postnatal therapy must be used for optimum therapeutic outcomes in the treatment of patients with SMA. ANN NEUROL 2026;100:584-599.