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Predicted deleterious variants in the human genome relevant to gene therapy with adeno-associated virus vectors

Based on the observation that humans have variable responses of gene expression with the same dose of an adeno-associated vector, we hypothesized that there are deleterious variants in genes coding for processes required for adeno-associated virus (AAV)-mediated gene transfer/expression that may ham...

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Published in:Molecular therapy. Methods & clinical development 2023-12, Vol.31, p.101136-101136, Article 101136
Main Authors: Rostami, Mahboubeh R., Leopold, Philip L., Vasquez, Jenifer M., de Mulder Rougvie, Miguel, Al Shakaki, Alya, Hssain, Ali Ait, Robay, Amal, Hackett, Neil R., Mezey, Jason G., Crystal, Ronald G.
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Language:English
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Summary:Based on the observation that humans have variable responses of gene expression with the same dose of an adeno-associated vector, we hypothesized that there are deleterious variants in genes coding for processes required for adeno-associated virus (AAV)-mediated gene transfer/expression that may hamper or enhance the effectiveness of AAV-mediated gene therapy. To assess this hypothesis, we evaluated 69,442 whole genome sequences from three populations (European, African/African American, and Qatari) for predicted deleterious variants in 62 genes known to play a role in AAV-mediated gene transfer/expression. The analysis identified 5,564 potentially deleterious mutations of which 27 were classified as common based on an allele frequency ≥1% in at least one population studied. Many of these deleterious variants are predicated to prevent while others enhance effective AAV gene transfer/expression, and several are linked to known hereditary disorders. The data support the hypothesis that, like other drugs, human genetic variability contributes to the person-to-person effectiveness of AAV gene therapy and the screening for genetic variability should be considered as part of future clinical trials. [Display omitted] Rostami and colleagues hypothesize that variability in clinical responses following AAV-mediated gene transfer might be a consequence of naturally occurring genetic variants in proteins that play a role in AAV infection. Evaluation of 62 genes revealed 5,563 variants in 69,442 genomes that might account for variable responses in human gene therapy trials.
ISSN:2329-0501
2329-0501
DOI:10.1016/j.omtm.2023.101136