Advantages and disadvantage ral vectors for gene therapy
Answers
Oncoretroviral vectors
Advantages Disadvantages
Efficient and stable gene transfer
Transduction rates of up to 40% of HSCs in non-human primates
Low rates of expression
One or fewer copies of provirus per cell
Sensitive to chromosomal position effects
Sensitive to DNA repeats, introns
High fidelity gene transfer due to intact integration and absence of chromosomal rearrangements Limits on the size of the therapeutic gene (< 7 kb) insert
Extensive clinical experience suggests that they are generally safe Difficult to deliver in vivo due to low titers (<107 TU/ml)
Safety concerns.
Potential problems with insertional mutagenesis due to integration inside or near a proto-oncogene
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Lentiviral vectors
Advantages Disadvantages
Efficient and stable gene transfer
Transduction rates of up to 90% of HSCs
High levels of transgene’s expression
High titers (>108 TU/ml)
Extensive clinical experience due to AIDS
Sensitive to chromosomal position effects
High fidelity gene transfer due to intact integration and absence of chromosomal rearrangements Limits on the size of the therapeutic gene (< 10 kb) insert
Safety concerns.
Potential problems with insertional mutagenesis due to integration inside or near a proto-oncogene
.
Adenoviral vectors
Advantages Disadvantages
High efficiency of gene transfer
Delivery of many genome copies per target cell, that typically translates into very high expression
Relatively large therapeutic genes (25-30 kb with the latest generation vectors)
High fidelity of gene transfer
Vector genomes are genetically stable
Transfer and expression are transient
Since adenoviruses are non-integrating viruses, the transgene expression typically lasts 1-2 months in non-dividing cells, while is much shorter in dividing cells
In vivo administration The pre-existing immunity against adenoviruses in individuals may result in low levels of transgene delivery and expression
Extensive clinical experience Vectors are immunogenic since the virus capsid and remaining viral proteins cause inflammation
No issues with insertional mutagenesis Safety issues: Vectors are lethal at high doses and are highly infectious
Adeno Associated Vectors (AAV)
Advantages Disadvantages
Highly efficient gene transfer
Several genome copies per target cell
Small transgenes (£ 4.7 kb)
High fidelity gene transfer
Vector genomes are genetically stable
Stable expression in some settings
Able to integrate into target cell genome
Transfer and expression are not always stable as the virus does not always integrate
Questionable tropism for HSC
In vivo administration Frequently immunogenic
Generally safe at doses tested The pre-existing immunity in individuals may result in low levels of transgene delivery and expression
Safety concerns:
Potential problems with insertional mutagenesis and small chromosomal rearrangements
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