170 research outputs found
Combinatorial treatment for spinal muscular atrophy
No full textSpinal muscular atrophy (SMA) is a severe autosomal recessive motor neuron disease caused by loss of SMN1, which encodes a protein essential for motor neuron survival. SMA patients have one or more copies of an alternate SMN gene, SMN2, which is nearly identical to SMN1. SMN2 differs at a single nucleotide from SMN1 which results in the skipping of exon 7 in the mRNA and produces an unstable protein (SMNΔ7). Therapeutic approaches that have been undertaken include i) replacement of SMN1 by gene delivery mediated by adeno-associated virus serotype 9 (AAV9) (Zolgensma), ii) correction of the aberrant SMN2 splicing using an antisense oligonucleotide (ASO) or small molecule (nusinersin, risdiplam), and iii) increased expression of SMN2 mediated by histone deacetylase (HDAC) inhibitors. Two of these three approaches have given rise to successful treatments for SMA, but they are very expensive, and their long-term safety is not well known. In addition, the ability of ASOs and viral vectors to reach their targets in the CNS with peripheral administration is limited. Small molecules may cross the brain blood barrier when orally delivered and can be discontinued if needed to mitigate adverse effects. This Editorial highlights the current study by Pagliarni et al. in which they used combined treatment of cell models of SMA with an ASO and an orally delivered HDAC inhibitor (panobinostat) to overcome the limitations of a single therapeutic approach. Panobinostat enhanced the expression of SMN2, increasing the amount of SMN2 mRNA available for splicing correction mediated by the ASO. In addition, panobinostat increased exon 7 retention in the SMN2 mRNA. This combinatorial treatment might allow lower or less frequent ASO doses, reducing the need for repeated intrathecal administration. The combined effects of panobinostat and nusinersen can now be tested in SMA animal models to determine whether this approach will be translatable to patients
MEMO Magazine
No full textKenneth Adams; Eleanor Brown Hibben; George Fischbeck; Colonel and Mrs. John G. Whit
Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy
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Targeting the 5' untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy
No full textNucleic acid therapeutics allow sequence-based targeting of disease genes, such as the genes involved in spinal muscular atrophy (SMA) pathogenesis. SMA is a neuromuscular disorder caused by mutations in the survival motor neuron 1 gene (SMN1). All patients have at least one copy of a paralog, SMN2, but a C-to-T transition in this gene results in exon 7 skipping in a majority of transcripts. As a result, only 10 to 20 percent of SMN2 transcripts encode the fully functional SMN protein. Nusinersen, an FDA-approved therapeutic for SMA, is an antisense oligonucleotide (ASO) that promotes exon 7 inclusion in the SMN2 transcript. The ceiling effect associated with splice-switching approaches makes complementary therapeutic strategies necessary. Increasing the total pool of SMN2 transcripts and increasing the translational efficiency of these transcripts are strategies that can be used in combination with splice correction. I sought to determine whether the 5’ untranslated region (5’UTR) of SMN2 contains an element that reduces its expression that can be targeted as a means of increasing SMN levels. I found that ASOs targeting the 5’ end of SMN2 increase SMN mRNA and protein levels, and that this effect is due to ASO-mediated inhibition of SMN2 mRNA decay. Moreover, using the 5’UTR ASO in combination with a splice-switching oligonucleotide (SSO) increases SMN levels above those attained with the SSO alone. I show that the effect of this 5’UTR ASO is human-specific. These results add to the current understanding of SMN regulation and point toward a new therapeutic target for SMA
B2 attenuates polyglutamine-expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy
No full textAkt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity
No full textSpinal and bulbar muscular atrophy (SBMA) is a progressive neurodegenerative disease caused by an expansion of the polyglutamine tract in the androgen receptor (AR). Here we investigated the regulation of AR phosphorylation in order to understand factors that may modify SBMA disease progression. We show that expanded polyglutamine AR is phosphorylated by Akt. Substitution of the AR at two Akt consensus sites, S215 and S792, with aspartate, which mimics phosphorylation, reduces ligand binding, ligand-dependent nuclear translocation, transcriptional activation, and toxicity of expanded polyglutamine AR. Co-expression of constitutively active Akt and the AR has similar consequences, which are blocked by alanine substitutions at residues 215 and 792. Furthermore, in motor neuron-derived MN-1 cells toxicity associated with polyglutamine-expanded AR is rescued by co-expression with Akt. Insulin-like growth factor 1 (IGF-1) stimulation, which activates several cell survival promoting pathways, also reduces toxicity of the expanded polyglutamine AR in MN-1 cells, in a manner dependent upon phospho-inositol-3’ kinase. IGF-1 rescue of AR toxicity is diminished by alanine substitutions at the Akt consensus sites. These results highlight potential targets for therapeutic intervention in SBM
Overexpression of IGF-1 in Muscle Attenuates Disease in a Mouse Model of Spinal and Bulbar Muscular Atrophy
No full textExpansion of a polyglutamine tract in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA). We previously showed that Akt-mediated phosphorylation of AR reduces ligand binding and attenuates the mutant AR toxicity. Here, we show that in culture insulin-like growth factor 1 (IGF-1) reduces AR aggregation and increases AR clearance via the ubiquitin-proteasome system through phosphorylation of AR by Akt. In vivo, SBMA transgenic mice overexpressing a muscle-specific isoform of IGF-1 selectively in skeletal muscle show evidence of increased Akt activation and AR phosphorylation and decreased AR aggregation. Augmentation of IGF-1/Akt signaling rescues behavioral and histopathological abnormalities, extends the life span, and reduces both muscle and spinal cord pathology of SBMA mice. This study establishes IGF-1/Akt-mediated inactivation of mutant AR as a strategy to counteract disease in vivo and demonstrates that skeletal muscle is a viable target tissue for therapeutic intervention in SBMA
Therapeutic approaches to spinal and bulbar muscular atrophy.
No full textSpinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism probably involves a toxic gain of function in the mutant protein, because other mutations that cause a loss of androgen receptor function result in a different phenotype and the mutant protein is toxic in mouse models. In these models, the toxicity is ligand-dependent and is associated with protein aggregation, as well as altered transcriptional regulation, axonal transport and mitochondrial function. Various therapeutic approaches have shown efficacy in mouse models, including androgen reduction, heat shock protein 90 (HSP90) inhibition and insulin-like growth factor (IGF)-1 overexpression. Clinical trials of androgen-reducing agents have had mixed results, with indications of efficacy but no proof of clinically meaningful benefit to date. These clinical studies have established outcome measures for future trials of other agents that have been beneficial in animal studies
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