SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet?

Abstract

Spinal muscular atrophy (SMA) remains one of the most common and lethal autosomal recessive diseases. Homozygous deletion of survival of motor neuron 1 (SMN1) and resulting SMN protein deficiency manifests predominantly with motor neuron degeneration; however, a wealth of emerging data supports a broader influence of SMN deficiency in disease pathogenesis. In this issue of the JCI, Kariya and colleagues demonstrate the relatively selective impact of SMN depletion on the distal motor unit using a series of SMN2-expressing transgenic mice in which constitutive SMN knockdown follows variable periods of normal development. Their observations provide further insights regarding the temporal requirements for SMN in mice, renewing speculation about when and where repletion of SMN is necessary for optimal outcomes in SMA patients.