Subcutaneous administration of TC007 reduces disease severity in an animal model of SMA.
BACKGROUND
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infantile death. It is caused by the loss of functional Survival Motor Neuron 1 (SMN1). There is a nearly identical copy gene, SMN2, but it is unable to rescue from disease due to an alternative splicing event that excises a necessary exon (exon 7) from the majority of SMN2-derived transcripts. While SMNDelta7 protein has severely reduced functionality, the exon 7 sequences may not be specifically required for all activities. Therefore, aminoglycoside antibiotics previously shown to suppress stop codon recognition and promote translation read-through have been examined to increase the length of the SMNDelta7 C-terminus.


RESULTS
Here we demonstrate that subcutaneous-administration of a read-through inducing compound (TC007) to an intermediate SMA model (Smn-/-; SMN2+/+; SMNDelta7) had beneficial effects on muscle fiber size and gross motor function.


CONCLUSIONS
Delivery of the read-through inducing compound TC007 reduces the disease-associated phenotype in SMA mice, however, does not significantly extend survival.
Mattis
Virginia B
VB
Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia MO, USA. virginiamattis@gmail.com
Fosso
Marina Y
MY
Chang
Cheng-Wei
CW
Lorson
Christian L
CL
D000617:Aminoglycosides / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000378:metabolism; D013194:Staining and Labeling; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism
D000617:Aminoglycosides; D055533:Survival of Motor Neuron 1 Protein; C546326:TC007