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Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model.

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.

SUBMITTER: Mattis VB

PROVIDER: S-EPMC2748896 | biostudies-other | 2009 Oct

REPOSITORIES: biostudies-other

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Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model.

Mattis Virginia B VB Ebert Allison D AD Fosso Marina Y MY Chang Cheng-Wei CW Lorson Christian L CL

Human molecular genetics 20090721 20

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 t ...[more]

PMID: 19625298

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Project description:BackgroundSpinal Muscular Atrophy (SMA) is a devastating neuromuscular disease caused by hypomorphic loss of function in the Survival Motor Neuron (SMN) protein. SMA presents across broad spectrum of disease severity. Unfortunately, vertebrate models of intermediate SMA have been difficult to generate and are thus unable to address key aspects of disease etiology. To address these issues, we developed a Drosophila model system that recapitulates the full range of SMA severity, allowing studies of pre-onset biology as well as late-stage disease processes.ResultsHere, we carried out transcriptomic and proteomic profiling of mild and intermediate Drosophila models of SMA to elucidate molecules and pathways that contribute to the disease. Using this approach, we elaborated a role for the SMN complex in the regulation of innate immune signaling. We find that mutation or tissue-specific depletion of SMN induces hyperactivation of the Immune Deficiency (IMD) and Toll pathways, leading to overexpression of antimicrobial peptides (AMPs) and ectopic formation of melanotic masses in the absence of an external challenge. Furthermore, knockdown of downstream targets of these signaling pathways reduced melanotic mass formation caused by SMN loss. Importantly, we identify SMN as a negative regulator of an ubiquitylation complex that includes Traf6, Bendless and Diap2, and plays a pivotal role in several signaling networks.ConclusionsIn alignment with recent research on other neurodegenerative diseases, these findings suggest that hyperactivation of innate immunity contributes to SMA pathology. This work not only provides compelling evidence that hyperactive innate immune signaling is a primary effect of SMN depletion, but it also suggests that the SMN complex plays a regulatory role in this process in vivo. In summary, immune dysfunction in SMA is a consequence of reduced SMN levels and is driven by cellular and molecular mechanisms that are conserved between insects and mammals.

Dataset Information

Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model.

Publications

Delivery of a read-through inducing compound, TC007, lessens the severity of a spinal muscular atrophy animal model.

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