. NEURODEGENERATION. One target for amyotrophic lateral sclerosis therapy?. Science. 2016 Aug 12;353(6300):647-8. PubMed.


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  1. This is really exceptionally nice science. It’s certainly possible to consider this a drug target except for the following possible caveats:

    1) The antisense oligonucleotides are not that effective at knockdown of SUPT4H1, at least as compared to the ASO for the actual C9 expasion itself, which can very specifically knock down more than 90 percent of the transcript and the downstream toxicity, be it from RNA or dipeptide repeats. Of course that does not rule out the possibility that a better ASO for SUPT4H1 could be generated.

    2) The possibility that inhibiting this gene—which can handle many other expansion repeats—could prove to be neurotoxic or cytotoxic, because there could be so many “off-target” actions. My experience suggests most companies would shy away from a drug with real possible off-target toxicity. This problem is far, far less likely with the C9 ASOs.

    Could there be a therapeutic advantage to knocking down both sense and antisense transcripts? Certainly yes—if in fact the antisense strand contributes to real disease and not artificially generated models of antisense toxicity. But accumulating data from ASO to sense C9 suggests that the vast majority of actual DPRs originate from the sense strand, and as yet there is no real evidence for endogenous toxicity of the DPR synthesized from the antisense strand.

    After studying neurodegeneration for years, I learned the hard lesson that unfortunately, fine science does not equate to real drug therapies in humans. Mice, flies, and yeast go only so far in defining a real human therapy, but only future work will be able to address that. The present Gitler/Petrucelli work certainly suggests we should consider that additional course. It’s great to have the additional druggable targets this work provides.

    View all comments by Jeffrey D. Rothstein

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  1. Tackling Mutant C9ORF72 Transcripts at the Source