@article {1503185,
	title = {CRISPR/Cas9 Mediated Disruption of the Swedish APP Allele as a Therapeutic Approach for Early-Onset Alzheimer{\textquoteright}s Disease},
	journal = {Mol Ther Nucleic Acids},
	volume = {11},
	year = {2018},
	month = {2018 Jun 01},
	pages = {429-440},
	abstract = {The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes dominantly inherited Alzheimer{\textquoteright}s disease (AD) as a result of increased β-secretase cleavage of the amyloid-β (Aβ) precursor protein. This leads to abnormally high Aβ levels, not only in brain but also in peripheral tissues of mutation carriers. Here, we selectively disrupted the human mutant APP allele using CRISPR. By applying CRISPR/Cas9~from Streptococcus pyogenes, we generated allele-specific deletions of either APP or APP. As measured by ELISA, conditioned media of targeted patient-derived fibroblasts displayed an approximate 60\% reduction in secreted Aβ. Next, coding sequences for the APP-specific guide RNA (gRNA) and Cas9 were packaged into separate adeno-associated viral (AAV) vectors. Site-specific indel formation was achieved both in primary neurons isolated from APP transgenic mouse embryos (Tg2576) and after co-injection of these vectors into hippocampus of adult mice. Taken together, we here present proof-of-concept data that CRISPR/Cas9 can selectively disrupt the APP allele both ex~vivo and in~vivo-and thereby decrease pathogenic Aβ. Hence, this system may have the potential to be developed as a tool for gene therapy against AD caused by APPswe and other point mutations associated with increased Aβ.},
	issn = {2162-2531},
	doi = {10.1016/j.omtn.2018.03.007},
	author = {Gy{\"o}rgy, Bence and L{\"o}{\"o}v, Camilla and Zaborowski, Miko{\l}aj P and Takeda, Shuko and Kleinstiver, Benjamin P and Commins, Caitlin and Kastanenka, Ksenia and Mu, Dakai and Volak, Adrienn and Giedraitis, Vilmantas and Lannfelt, Lars and Maguire, Casey A and Joung, J Keith and Hyman, Bradley T and Breakefield, Xandra O and Ingelsson, Martin}
}
