Open AccessAntisense Oligonucleotide-Induced Amyloid Precursor Protein Splicing Modulation as a Therapeutic Approach for Dutch-Type Cerebral Amyloid Angiopathy
Author(s) -
Elena Daoutsali,
Tsinatkeab T Hailu,
Ronald A.M. Buijsen,
Barry A. Pepers,
Linda M. van der Graaf,
Marcel M. Verbeek,
Daniel Curtis,
Thomas de Vlaam,
Willeke M. C. van RoonMom
Publication year - 2021
Publication title -
nucleic acid therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.255
H-Index - 67
eISSN - 2159-3345
pISSN - 2159-3337
DOI - 10.1089/nat.2021.0005
Subject(s) - exon , cerebral amyloid angiopathy , gene isoform , alternative splicing , amyloid precursor protein , point mutation , biology , mutation , microbiology and biotechnology , exon skipping , amyloid (mycology) , rna splicing , rna , cancer research , gene , alzheimer's disease , genetics , pathology , medicine , disease , dementia , botany
Dutch-type cerebral amyloid angiopathy (D-CAA) is a monogenic form of cerebral amyloid angiopathy and is inherited in an autosomal dominant manner. The disease is caused by a point mutation in exon 17 of the amyloid precursor protein ( APP ) gene that leads to an amino acid substitution at codon 693. The mutation is located within the amyloid beta (Aβ) domain of APP, and leads to accumulation of toxic Aβ peptide in and around the cerebral vasculature. We have designed an antisense oligonucleotide (AON) approach that results in skipping of exon 17, generating a shorter APP isoform that lacks part of the Aβ domain and the D-CAA mutation. We demonstrate efficient AON-induced skipping of exon 17 at RNA level and the occurrence of a shorter APP protein isoform in three different cell types. This resulted in a reduction of Aβ40 in neuronally differentiated, patient-derived induced pluripotent stem cells. AON-treated wild-type mice showed successful exon skipping on RNA and protein levels throughout the brain. These results illustrate APP splice modulation as a promising therapeutic approach for D-CAA.