Paper
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György B, Lööv C, Zaborowski MP, Takeda S, Kleinstiver BP, Commins C, Kastanenka K, Mu D, Volak A, Giedraitis V, Lannfelt L, Maguire CA, Joung JK, Hyman BT, Breakefield XO, Ingelsson M. CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer’s Disease. Mol Ther Nucleic Acids. Volume 11, p429–440, 1 June 2018
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University Copenhagen
I think the György et al. paper is quite exciting. They clearly show that they can target specifically the mutant allele in fibroblasts and that these express lower amounts of Aβ40 and Aβ42. So the in vitro part is quite convincing. The in vivo part is not so clear, since they state that it is difficult for them to measure delivery of the CRISPR constructs by the AAV virus. It would be interesting to see more systematic analyses of the targeted cells in the hippocampus. How far can the virus spread and alter the mutant allele?
They also claim that it was advantageous to target the Swedish APP mutation since it is a mutation affecting two nucleotides. This keeps me wondering how effective the approach is when only a single nucleotide is affected. I also did not see any off-target screening in the paper and I was wondering if that was addressed. Obviously this is a concern, even though the latest research has shown that there are few, if any, off-target effects it would have been important to check. Also, one needs to keep in mind that AD is rarely caused by such familial mutations, but for the few affected individuals this could be an appropriate therapy.
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