Spinal muscular atrophy: development and implementation of potential treatments

Abstract

In neurodegenerative disorders, effective treatments are urgently needed, along with methods to determine whether treatment worked. In this review, we discuss the rapid progress in the understanding of recessive proximal spinal muscular atrophy and how this is leading to exciting potential treatments of the disease. Spinal muscular atrophy is caused by loss of the survival motor neuron 1 (SMN1) gene and reduced levels of SMN protein. The critical downstream targets of SMN deficiency that result in motor neuron loss are not known. However, increasing SMN levels has a marked impact in mouse models, and these therapeutics are rapidly moving toward clinical trials. Promising preclinical therapies, the varying degree of impact on the mouse models, and potential measures of treatment effect are reviewed. One key issue discussed is the variable outcome of increasing SMN at different stages of disease progression.

Figure 1

Timing of SMN Restoration and Predicted Outcomes: SMA is caused by reduced levels of SMN protein. Therapies that provide early restoration of SMN are anticipated to fully rescue motor neurons and the motor unit. When SMN restoration is delayed it is anticipated that rescue will be reduced in a time-dependent fashion. CMAP: compound muscle action potential; MUNE: motor unit number estimation. *Following delayed treatment, CMAP size may be fully corrected if there is sufficient collateral reinnervation from the remaining motor neurons.