Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Spinal Muscular Atrophy (SMA) is a rare inherited neuromuscular disorder caused by insufficient Survival of Motor Neuron (SMN) protein due to SMN1 gene defects.
• The SMN2 gene produces low levels of functional SMN protein, which cannot fully compensate for the SMN1 deficiency.
• Risdiplam is an oral small molecule designed to modify SMN2 pre-mRNA splicing, aiming to increase functional SMN protein levels.

Purpose of the Study:

• To investigate the in vitro characteristics of risdiplam.
• To determine risdiplam's in vivo drug levels and distribution across various tissues.
• To assess the effect of risdiplam on SMN protein expression in preclinical models of SMA.

Main Methods:

• In vitro assessment of risdiplam characteristics.
• In vivo pharmacokinetic studies in mice, rats, and monkeys to measure drug levels in plasma, brain, and muscle.
• Evaluation of risdiplam's effect on SMN protein levels in CNS and peripheral tissues of SMA mouse models.

Main Results:

• Risdiplam demonstrated similar total drug levels in plasma, muscle, and brain across different animal species.
• Cerebrospinal fluid (CSF) levels of risdiplam in monkeys correlated with free plasma concentrations, indicating CNS penetration.
• Dosing with risdiplam resulted in a dose-dependent increase in SMN protein levels in both CNS and peripheral tissues of SMA mouse models.

Conclusions:

• Preclinical data indicate that risdiplam effectively distributes to the central nervous system and peripheral tissues.
• The observed increase in SMN protein in animal models suggests risdiplam's potential to address the underlying pathology of SMA.
• These findings support the translation of risdiplam's efficacy observed in blood to relevant tissues in SMA patients.