Disease mechanisms and therapeutic approaches in spinal muscular atrophy

Abstract

Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal-recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease.

Figure 1.

Schematic representation of the key morphological and functional abnormalities induced by SMN deficiency in the motor system of SMA mouse models. Multiple aspects of the motor system are disrupted in SMA. For simplicity, only the excitatory premotor neurons of the motor circuit affected by the disease are depicted. Motor neurons (dark blue) in the ventral horn of the spinal cord receive excitatory synaptic inputs from proprioceptive neurons residing in the dorsal root ganglion (green) and local interneurons (light blue). Upon sufficient excitatory drive to generate action potentials, motor neurons innervating skeletal muscle induce muscle contraction through cholinergic neurotransmission at the NMJ. The specific deficits within the SMA motor system are indicated and are described in detail in the text.

Figure 2.

The biogenesis of snRNPs requires SMN and is disrupted in SMA motor neurons. A, Schematic representation of the only molecularly established RNP assembly functions of SMN. The multisubunit SMN complex (Pellizzoni, 2007) binds to seven Sm proteins (B, D1, D2, D3, E, F, G) or a subset of Sm proteins and LSm10/11 to mediate their respective assembly onto specific snRNAs, yielding spliceosomal snRNPs that function in pre-mRNA splicing or U7 snRNP that functions in histone mRNA processing. B, SMN deficiency causes a more prominent reduction of snRNPs in the nucleus of SMA motor neurons than other spinal ventral horn cells. Double-label immunohistochemistry and confocal microscopy analysis of lumbar L1 spinal cord sections from wild-type (WT) or SMNΔ7 SMA mice (Le et al., 2005) at postnatal day 10 was performed using antibodies against SmB (Carissimi et al., 2006) to label snRNPs and the motor-neuron-specific marker ChAT, as described previously (Ruggiu et al., 2012).

Figure 3.

Candidate SMA therapeutics and their progress through the clinical development pipeline. The chart summarizes the current status of the most advanced programs in SMA therapeutic development based on publicly available information. Small molecules and biologics listed with blue bars aim to increase the functional levels of SMN, and those denoted with red bars act by improving motor system function through SMN-independent mechanisms.