In silico reconstruction of the viral evolutionary lineage yields a potent gene therapy vector

Details

• Alternative Title:
  Cell Rep
• Personal Author:
  Zinn, Eric ; Pacouret, Simon ; Khaychuk, Vadim ; Turunen, Heikki T. ; Carvalho, Livia S. ; Andres-Mateos, Eva ; Shah, Samiksha ; Shelke, Rajani ; Maurer, Anna C. ; Plovie, Eva ; Xiao, Ru ; Vandenberghe, Luk H. ; Zinn, Eric ; Pacouret, Simon ; Khaychuk, Vadim ; Turunen, Heikki T. ; Carvalho, Livia S. ; Andres-Mateos, Eva ; Shah, Samiksha ; Shelke, Rajani ; Maurer, Anna C. ; Plovie, Eva ; Xiao, Ru ; Vandenberghe, Luk H.
• Description:
  Adeno-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.
• Subjects:
  Dependovirus Genetic Therapy Genetic Vectors Gene Transfer Techniques Molecular Sequence Data
• Keywords:
  AAV Adeno-associated Virus Ancestral Reconstruction Capsid T-cell Gene Therapy Gene Transfer Neutralizing Antibody Pre-existing Immunity Synthetic Biology Vaccine Vector Virus

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• Source:
  Cell Rep. 12(6):1056-1068 ; Cell Rep. 12(6):1056-1068
• Pubmed ID:
  26235624
• Pubmed Central ID:
  PMC4536165
• Document Type:
  Journal Article
• Funding:
  DP1 EY023177/EY/NEI NIH HHSUnited States/ ; DP1 OD008267/OD/NIH HHSUnited States/ ; 5DP1EY023177-03/DP/NCCDPHP CDC HHSUnited States/
• Volume:
  12
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:6bd8345ff25df1affcd69bb4cea2b823da7ab4655623c06da33bb2486e8d9836
• Download URL:
  https://stacks.cdc.gov/view/cdc/35070/cdc_35070_DS1.pdf
• File Type:
  [PDF - 2.53 MB ]