GluA4-Targeted AAV Vectors Deliver Genes Selectively to Interneurons while Relying on the AAV Receptor for Entry
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GluA4-Targeted AAV Vectors Deliver Genes Selectively to Interneurons while Relying on the AAV Receptor for Entry. / Hartmann, Jessica; Thalheimer, Frederic B.; Höpfner, F.; Kerzel, Thomas; Khodosevich, Konstantin; García-González, D.; Monyer, Hannah; Diester, Ilka; Büning, Hildegard; Carette, J. E.; Fries, Pascal; Buchholz, Christian J.
In: Molecular Therapy - Methods & Clinical Development, Vol. 14, 2019, p. 252-260.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - GluA4-Targeted AAV Vectors Deliver Genes Selectively to Interneurons while Relying on the AAV Receptor for Entry
AU - Hartmann, Jessica
AU - Thalheimer, Frederic B.
AU - Höpfner, F.
AU - Kerzel, Thomas
AU - Khodosevich, Konstantin
AU - García-González, D.
AU - Monyer, Hannah
AU - Diester, Ilka
AU - Büning, Hildegard
AU - Carette, J. E.
AU - Fries, Pascal
AU - Buchholz, Christian J.
PY - 2019
Y1 - 2019
N2 - Selective gene delivery into subtypes of interneurons remains an important challenge in vector development. Adeno-associated virus (AAV) vector particles are especially promising for intracerebral injections. For cell entry, AAV2 particles are supposed to attach to heparan-sulfate proteoglycans (HSPGs) followed by endocytosis via the AAV receptor (AAVR). Here, we assessed engineered AAV particles deficient in HSPG attachment but competent in recognizing the glutamate receptor 4 (GluA4, also known as GluRD or GRIA4) through a displayed GluA4-specific DARPin (designed ankyrin repeat protein). When injected into the mouse brain, histological evaluation revealed that in various regions, more than 90% of the transduced cells were interneurons, mainly of the parvalbumin-positive subtype. Although part of the selectivity was mediated by the DARPin, the chosen spleen focus-forming virus (SFFV) promoter had contributed as well. Further analysis revealed that the DARPin mediated selective attachment to GluA4-positive cells, whereas gene delivery required expression of AAVR. Our data suggest that cell selectivity of AAV particles can be modified rationally and efficiently through DARPins, but expression of the AAV entry receptor remains essential.
AB - Selective gene delivery into subtypes of interneurons remains an important challenge in vector development. Adeno-associated virus (AAV) vector particles are especially promising for intracerebral injections. For cell entry, AAV2 particles are supposed to attach to heparan-sulfate proteoglycans (HSPGs) followed by endocytosis via the AAV receptor (AAVR). Here, we assessed engineered AAV particles deficient in HSPG attachment but competent in recognizing the glutamate receptor 4 (GluA4, also known as GluRD or GRIA4) through a displayed GluA4-specific DARPin (designed ankyrin repeat protein). When injected into the mouse brain, histological evaluation revealed that in various regions, more than 90% of the transduced cells were interneurons, mainly of the parvalbumin-positive subtype. Although part of the selectivity was mediated by the DARPin, the chosen spleen focus-forming virus (SFFV) promoter had contributed as well. Further analysis revealed that the DARPin mediated selective attachment to GluA4-positive cells, whereas gene delivery required expression of AAVR. Our data suggest that cell selectivity of AAV particles can be modified rationally and efficiently through DARPins, but expression of the AAV entry receptor remains essential.
KW - AAV
KW - AAVR
KW - GluA4
KW - interneuron
KW - parvalbumin
KW - PV
KW - targeting
U2 - 10.1016/j.omtm.2019.07.004
DO - 10.1016/j.omtm.2019.07.004
M3 - Journal article
C2 - 31463334
AN - SCOPUS:85070571965
VL - 14
SP - 252
EP - 260
JO - Molecular Therapy - Methods & Clinical Development
JF - Molecular Therapy - Methods & Clinical Development
SN - 2329-0501
ER -
ID: 226872807