The motor neuron disease spinal muscular atrophy (SMA) is the leading inherited cause of death in infancy and childhood. It is caused by recessive mutations of the survival motor neuron 1 gene (SMN1). All patients retain one or more copies of the homologous SMN2 gene, but it produces inadequate levels of SMN protein due to an alternative splice event. Novel therapeutics aiming to modulate SMN2 splicing including antisense oligonucleotides and small molecules are recently FDA-approved or currently in clinical trials in SMA patients. While this is a success, it remains unknown why many patients have inadequate therapeutic responses. Defining the optimal timing and tissue targeting of SMN induction has been limited by poor understanding of early disease pathology in patients. To address this knowledge gap, in preliminary studies we examined ventral root axons in severe SMA patients and model mice and discovered marked impairments of motor axon sorting and radial growth, which begin prenatally and are followed by degeneration of immature axons perinatally. This project aims to determine if these pathologies may underlie the early disease onset, stereotypical pattern of weakness, and precipitous decline of severe SMA patients.
In Specific Aim 1, we will characterize the temporal and topographic patterns of this pathology in both a severe and milder SMA mouse model and in human samples.
In Specific Aim 2, we will define the cellular contributors to this pathology utilizing a series of conditional SMA mouse lines expressing increased SMN specifically in either motor neurons, Schwann cells, or muscle. We will also evaluate whether neuregulin 1 type III (NRG1-III), a key regulator of peripheral axon development, is dysregulated in SMA and explore whether overexpression of NRG1-III can ameliorate SMA axonal pathologies. Finally, in Specific Aim 3, we will establish when SMN- inducing drugs, including SMN2 splice-switching antisense oligonucleotides and the small molecule SMN-C3, must be delivered to restore axonal maturation, prevent motor unit degeneration, and provide optimal phenotypic rescue. Together, these studies will characterize a newly recognized and prominent pathology of severe SMA patients and define the optimal timing of therapeutics. The results of these investigations will provide important insights regarding the outcomes of patients currently enrolled in clinical trials, influence the design of future trials, and potentially uncover novel SMA therapeutic targets.
The leading inherited cause of infant mortality, spinal muscular atrophy (SMA) Type I, causes early onset, severe muscle weakness. Although novel SMA therapeutics are recently FDA-approved or in clinical trials, the optimal timing of treatment in patients is unknown. We have demonstrated that motor axonal development is markedly impaired in SMA patients and mouse models, and here we will establish when and how these defects arise and determine when SMA therapeutics must be delivered to reverse this pathology.
