Molecular Biology, volume 56, issue 4, pages 559-571

Effective Viral Delivery of Genetic Constructs to Neuronal Culture for Modeling and Gene Therapy of GNAO1 Encephalopathy

Publication typeJournal Article
Publication date2022-04-29
Quartile SCImago
Q4
Quartile WOS
Q4
Impact factor1.2
ISSN00268933, 16083245
Structural Biology
Biophysics
Abstract
GNAO1 encephalopathy is an orphan genetic disease associated with early infantile epilepsy, impaired motor control, and severe developmental delay. The disorder is caused by mutations in the GNAO1 gene, leading to dysfunction of the encoded protein Gαo1. There is no cure for this disease, and symptomatic therapy is ineffective. Phenotypic heterogeneity highlights the need for a personalized approach for treating patients with a specific clinical variant of GNAO1 and requires the study of the disease mechanism in animal and cell models. Towards this aim, we developed an approach for modeling GNAO1 encephalopathy and testing gene therapy drugs in primary neurons derived from healthy mice. We optimized the delivery of transgenes to Gαo1-expressing neurons using recombinant adeno-associated viruses (rAAV). We assessed the tropism of five neurotropic AAV serotypes (1, 2, 6, 9, DJ) for Gαo1-positive neurons from the whole mouse brain. The DJ serotype showed the highest potential as a reporter delivery vehicle, infecting up to 66% of Gαo1-expressing cells without overt cytotoxicity. We demonstrated that AAV-DJ also provides efficient delivery and expression of genetic constructs encoding normal and mutant Gαo1, as well as short hairpin RNA (shRNA) to suppress endogenous Gnao1 in murine neurons. Our results will further simplify the study of the pathological mechanism for clinical variants of GNAO1, as well as optimize the testing of gene therapy approaches for GNAO1 encephalopathy in cell models.

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Lunev E. A. et al. Effective Viral Delivery of Genetic Constructs to Neuronal Culture for Modeling and Gene Therapy of GNAO1 Encephalopathy // Molecular Biology. 2022. Vol. 56. No. 4. pp. 559-571.
GOST all authors (up to 50) Copy
Lunev E. A., Shmidt A. A., Vassilieva S. G., Savchenko I. M., Loginov V. A., Marina V. I., Egorova T. V., Bardina M. V. Effective Viral Delivery of Genetic Constructs to Neuronal Culture for Modeling and Gene Therapy of GNAO1 Encephalopathy // Molecular Biology. 2022. Vol. 56. No. 4. pp. 559-571.
RIS |
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RIS Copy
TY - JOUR
DO - 10.1134/S0026893322040069
UR - https://doi.org/10.1134%2FS0026893322040069
TI - Effective Viral Delivery of Genetic Constructs to Neuronal Culture for Modeling and Gene Therapy of GNAO1 Encephalopathy
T2 - Molecular Biology
AU - Shmidt, A. A.
AU - Savchenko, I M
AU - Loginov, V A
AU - Egorova, T V
AU - Bardina, M V
AU - Lunev, E A
AU - Vassilieva, S G
AU - Marina, V I
PY - 2022
DA - 2022/04/29 00:00:00
PB - Pleiades Publishing
SP - 559-571
IS - 4
VL - 56
SN - 0026-8933
SN - 1608-3245
ER -
BibTex |
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BibTex Copy
@article{2022_Lunev
author = {A. A. Shmidt and I M Savchenko and V A Loginov and T V Egorova and M V Bardina and E A Lunev and S G Vassilieva and V I Marina},
title = {Effective Viral Delivery of Genetic Constructs to Neuronal Culture for Modeling and Gene Therapy of GNAO1 Encephalopathy},
journal = {Molecular Biology},
year = {2022},
volume = {56},
publisher = {Pleiades Publishing},
month = {apr},
url = {https://doi.org/10.1134%2FS0026893322040069},
number = {4},
pages = {559--571},
doi = {10.1134/S0026893322040069}
}
MLA
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MLA Copy
Lunev, E. A., et al. “Effective Viral Delivery of Genetic Constructs to Neuronal Culture for Modeling and Gene Therapy of GNAO1 Encephalopathy.” Molecular Biology, vol. 56, no. 4, Apr. 2022, pp. 559-571. https://doi.org/10.1134%2FS0026893322040069.
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