Faculty Collaboration Database

Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model. Hum Mol Genet 2009 Oct 15;18(20):3906-13

Date

07/25/2009

Pubmed ID

19625298

Pubmed Central ID

PMC2748896

DOI

10.1093/hmg/ddp333

Scopus ID

2-s2.0-70349575755 (requires institutional sign-in at Scopus site)   80 Citations

Abstract

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality and is caused by the loss of a functional SMN1 gene. In humans, there exists a nearly-identical copy gene known as SMN2 that encodes an identical protein as SMN1, but differs by a silent C to T transition within exon 7. This single nucleotide difference produces an alternatively spliced isoform, SMNDelta7, which encodes a rapidly degraded protein. The absence of the short peptide encoded by SMN exon 7 is critical in the disease development process; however, heterologous sequences can partially compensate for the SMN exon 7 peptide in several cellular assays. Consistent with this, aminoglycosides, compounds that can suppress efficient recognition of stop codons, resulted in significantly increased levels of SMN protein in SMA patient fibroblasts. We now examine the potential therapeutic capabilities of a novel aminoglycoside, TC007. In an intermediate SMA model (Smn-/-; SMN2+/+; SMNDelta7), when delivered directly to the central nervous system (CNS), TC007 induces SMN in both the brain and spinal cord, significantly increases lifespan ( approximately 30%) and increases ventral horn cell number, consistent with its ability to increase SMN levels in induced pluripotent stem cell-derived human SMA motor neuron cultures. Collectively, these experiments are the first in vivo examination of therapeutics for SMA designed to induce read-through of the SMNDelta7 stop codon to show increased benefit by direct administration to the CNS.

Author List

Mattis VB, Ebert AD, Fosso MY, Chang CW, Lorson CL

Author

Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aminoglycosides
Animals
Central Nervous System
Codon, Terminator
Disease Models, Animal
Humans
Mice
Mice, Transgenic
Muscular Atrophy, Spinal
Protein Biosynthesis
Severity of Illness Index
Survival of Motor Neuron 2 Protein