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| Status |
Public on Dec 13, 2022 |
| Title |
Efficient in vivo Genome Editing Prevents Hypertrophic Cardiomyopathy in Mice [Amplified_cDNA] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Dominant pathogenic variants encoding amino acid substitutions in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure, and sudden cardiac death. We assessed the efficacy of two different genetic therapies, an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9, to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more global editing especially in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
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| Overall design |
Editing efficiency of the targeted MYH6 R403Q allele and insertions/deletions (indels) after a single or multiple does of AAV9 ABE8e injection was assessed by sequencing PCR amplified cDNA of Myh6 derived from RNA extracted from specific cardiac chambers.
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| Contributor(s) |
Daniel R, Gregory A. N, Hiroko W, Mingyue L, Joshua M. G, Aditya R, Daniel M. D, David A. C, Júlia D C. M, Sajeev K, Lukas C, David C. P, Nerea Z, Luk V, David R. L, Jonathan G. S, Christine S |
| Citation(s) |
36797483 |
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| Submission date |
Dec 13, 2022 |
| Last update date |
Mar 14, 2023 |
| Contact name |
Daniel DeLaughter |
| Organization name |
Harvard Medical School
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| Department |
Genetics
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| Lab |
Seidman
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| Street address |
7 Avenue Louis Pasteur
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
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| Samples (78)
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| This SubSeries is part of SuperSeries: |
| GSE220851 |
Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
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| Relations |
| BioProject |
PRJNA911609 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE220811_Fig5_Amplified_cDNA_processed_data.xlsx |
28.7 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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