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Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models.

08:00 EDT 16th July 2018 | BioPortfolio

Summary of "Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models."

Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed next-generation SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy.

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Journal Details

This article was published in the following journal.

Name: The Journal of clinical investigation
ISSN: 1558-8238
Pages:

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Medical and Biotech [MESH] Definitions

Short fragments of DNA or RNA that are used to alter the function of target RNAs or DNAs to which they hybridize.

RNA molecules which hybridize to complementary sequences in either RNA or DNA altering the function of the latter. Endogenous antisense RNAs function as regulators of gene expression by a variety of mechanisms. Synthetic antisense RNAs are used to effect the functioning of specific genes for investigative or therapeutic purposes.

Thick triangular muscle in the SHOULDER whose function is to abduct, flex, and extend the arm. It is a common site of INTRAMUSCULAR INJECTIONS.

DNA that is complementary to the sense strand. (The sense strand has the same sequence as the mRNA transcript. The antisense strand is the template for mRNA synthesis.) Synthetic antisense DNAs are used to hybridize to complementary sequences in target RNAs or DNAs to effect the functioning of specific genes for investigative or therapeutic purposes.

Modified oligonucleotides in which one of the oxygens of the phosphate group is replaced with a sulfur atom.

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