. Targeting Amyloid-β Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-β Production. Mol Ther. 2018 Jun 6;26(6):1539-1551. Epub 2018 Mar 6 PubMed.


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  1. This is a very interesting study by Jennifer Chang, Michelle Hastings and colleagues, targeting APP using splice-switching antisense oligonucleotides. Traditionally, the field has focused on developing small molecule inhibitors of BACE; and although the biology of APP is relatively well understood, few studies have looked at APP as an alternative target. The idea of “tweaking” the APP molecule has the potential to overcome some of the side effects seen with BACE-1 inhibition, primarily due to the promiscuous nature of the latter.

    The work by Chang et al. is rigorous, and there is no question that the strategy is working. The fact that splice-switching antisense oligonucleotides have recently been approved for the treatment of SMA highlights the overall power of this strategy as a therapeutic tool. One limitation is that this strategy entirely abolishes the membrane-binding of APP and its proteolytic processing. This is likely to severely impact its normal function, as almost all known physiologic functions of APP are related to its membrane-targeting. As the authors’ point out, these approaches will be useful in cases where there is APP over-expression – such as Down’s syndrome or familial APP-duplication – since in these cases, reduction in copy number would restore the protein to normal levels. However, there is no over-expression of APP in the vast majority of Alzheimer’s cases, which are sporadic. Many studies have shown a role of the APP N-terminus in axon growth and signaling, and it is hard to imagine that an absence of a membrane-targeted APP would not negatively impact neuronal physiology.

    The main difference between this study and our recent preprint publication (Sun et al., 2018) is that we used CRISPR/Cas9 to edit the extreme C-terminus of APP, preserving the N-terminus and the membrane-targeting domains. This C-terminus editing specifically manipulates the balance between APP α/β-cleavage. As a result, our strategy inhibits the amyloidogenic (β-cleavage) pathway and enhanced the non-amyloidogenic (protective, α-cleavage) pathway. We also did a battery of physiologic studies and off-target analyses to ensure that the physiology of neurons was not severely disrupted by our approach. Similar experiments are also needed with the antisense oligonucleotide approach. Nevertheless, these recent studies using contemporary genetic tools are an exciting new development in the field, with significant therapeutic potential.

    View all comments by Subhojit Roy
  2. This approach is highly interesting - as it offers a radical way of suppressing the generation of Aβ and thereby reducing its associated neurotoxicity. The decrease of murine Aβ levels upon treatment of wild type mice was surprisingly robust even when the ASOs were delivered into the ventricles of adult animals, which is promising from a therapeutic perspective. Moreover, since it has already been proven feasible to use intrathecally delivered ASOs for the treatment of CNS disorders - as demonstrated by the development of nusinersen against SMN2 for spinal muscular dystrophy - it should be relatively straightforward to take the APP exon skipping ASOs to the clinical trial stage.

    However, potentially negative consequences of excluding exon 17 from APP mRNA will have to be carefully considered. Not only may the generation of a novel form of APP cause unforeseen harm, but also the complete suppression of amyloid-beta could have adverse effects - e.g. by removing a molecule that may have important antimicrobial effects in the CNS.

    View all comments by Martin Ingelsson

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