In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector
| Autor: | Simon Pacouret, Eva Andres-Mateos, Ru Xiao, Eva Plovie, Vadim Khaychuk, Luk H. Vandenberghe, Livia S. Carvalho, Rajani Shelke, Heikki Turunen, Samiksha Shah, Eric Zinn, Anna C. Maurer |
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| Rok vydání: | 2015 |
| Předmět: |
Ancestral reconstruction
Lineage (genetic) viruses In silico Genetic enhancement Genetic Vectors Molecular Sequence Data Biology medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology Virus 03 medical and health sciences Synthetic biology 0302 clinical medicine medicine Vector (molecular biology) lcsh:QH301-705.5 Adeno-associated virus 030304 developmental biology Genetics 0303 health sciences Gene Transfer Techniques Genetic Therapy Dependovirus 3. Good health lcsh:Biology (General) 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 12, Iss 6, Pp 1056-1068 (2015) |
| ISSN: | 2211-1247 |
| Popis: | SummaryAdeno-associated virus (AAV) vectors have emerged as a gene-delivery platform with demonstrated safety and efficacy in a handful of clinical trials for monogenic disorders. However, limitations of the current generation vectors often prevent broader application of AAV gene therapy. Efforts to engineer AAV vectors have been hampered by a limited understanding of the structure-function relationship of the complex multimeric icosahedral architecture of the particle. To develop additional reagents pertinent to further our insight into AAVs, we inferred evolutionary intermediates of the viral capsid using ancestral sequence reconstruction. In-silico-derived sequences were synthesized de novo and characterized for biological properties relevant to clinical applications. This effort led to the generation of nine functional putative ancestral AAVs and the identification of Anc80, the predicted ancestor of the widely studied AAV serotypes 1, 2, 8, and 9, as a highly potent in vivo gene therapy vector for targeting liver, muscle, and retina. |
| Databáze: | OpenAIRE |
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