دورية أكاديمية
RNA Interference Effectors Selectively Silence the Pathogenic Variant GNAO1 c.607 G > A In Vitro .
| العنوان: | RNA Interference Effectors Selectively Silence the Pathogenic Variant GNAO1 c.607 G > A In Vitro . |
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| المؤلفون: | Klementieva NV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia., Lunev EA; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia., Shmidt AA; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia., Loseva EM; Marlin Biotech LLC, Sochi, Russia., Savchenko IM; Marlin Biotech LLC, Sochi, Russia.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia., Svetlova EA; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia., Galkin II; Marlin Biotech LLC, Sochi, Russia.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia., Polikarpova AV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia., Usachev EV; Laboratory of Translational Biomedicine, Gamaleya National Research Center for Epidemiology, Moscow, Russia., Vassilieva SG; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia., Marina VI; Marlin Biotech LLC, Sochi, Russia., Dzhenkova MA; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia., Romanova AD; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia., Agutin AV; State Budgetary Healthcare Institution of Moscow Region 'Balashikha Hospital,' Balashikha, Russia., Timakova AA; Institute for Regenerative Medicine, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia., Reshetov DA; Marlin Biotech LLC, Sochi, Russia., Egorova TV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia., Bardina MV; Laboratory of Modeling and Gene Therapy of Hereditary Diseases, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.; Marlin Biotech LLC, Sochi, Russia.; Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia. |
| المصدر: | Nucleic acid therapeutics [Nucleic Acid Ther] 2024 Apr; Vol. 34 (2), pp. 90-99. Date of Electronic Publication: 2024 Jan 12. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 101562758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-3345 (Electronic) Linking ISSN: 21593337 NLM ISO Abbreviation: Nucleic Acid Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New Rochelle, N.Y. : Mary Ann Liebert, Inc. |
| مواضيع طبية MeSH: | Genetic Therapy* , Brain Diseases*/genetics, Animals ; Humans ; RNA Interference ; RNA, Small Interfering/pharmacology ; Alleles ; Genetic Vectors/genetics ; GTP-Binding Protein alpha Subunits, Gi-Go/genetics |
| مستخلص: | RNA interference (RNAi)-based therapeutics hold the potential for dominant genetic disorders, enabling sequence-specific inhibition of pathogenic gene products. We aimed to direct RNAi for the selective suppression of the heterozygous GNAO1 c.607 G > A variant causing GNAO1 encephalopathy. By screening short interfering RNA (siRNA), we showed that GNAO1 c.607G>A is a druggable target for RNAi. The si1488 candidate achieved at least twofold allelic discrimination and downregulated mutant protein to 35%. We created vectorized RNAi by incorporating the si1488 sequence into the short hairpin RNA (shRNA) in the adeno-associated virus (AAV) vector. The shRNA stem and loop were modified to improve the transcription, processing, and guide strand selection. All tested shRNA constructs demonstrated selectivity toward mutant GNAO1 , while tweaking hairpin structure only marginally affected the silencing efficiency. The selectivity of shRNA-mediated silencing was confirmed in the context of AAV vector transduction. To conclude, RNAi effectors ranging from siRNA to AAV-RNAi achieve suppression of the pathogenic GNAO1 c.607G>A and discriminate alleles by the single-nucleotide substitution. For gene therapy development, it is crucial to demonstrate the benefit of these RNAi effectors in patient-specific neurons and animal models of the GNAO1 encephalopathy. |
| فهرسة مساهمة: | Keywords: GNAO1 encephalopathy; RNA interference; RNA therapeutics; adeno-associated virus vectors; gene suppression; vectorized RNAi |
| المشرفين على المادة: | 0 (RNA, Small Interfering) 0 (GNAO1 protein, human) EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go) |
| تواريخ الأحداث: | Date Created: 20240112 Date Completed: 20240408 Latest Revision: 20240710 |
| رمز التحديث: | 20240710 |
| DOI: | 10.1089/nat.2023.0043 |
| PMID: | 38215303 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2159-3345 |
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| DOI: | 10.1089/nat.2023.0043 |