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Zinc finger nucleases have also been used in a mouse model of haemophilia [31] and a clinical trial found CD4+ human T-cells with the CCR5 gene disrupted by zinc finger nucleases to be safe as a potential treatment for HIV/AIDS. [32] ZFNs are also used to create a new generation of genetic disease models called isogenic human disease models.
In addition, zinc fingers have become extremely useful in various therapeutic and research capacities. Engineering zinc fingers to have an affinity for a specific sequence is an area of active research, and zinc finger nucleases and zinc finger transcription factors are two of the most important applications of this to be realized to date.
The restriction enzymes can be introduced into cells, for use in gene editing or for genome editing in situ, a technique known as genome editing with engineered nucleases. Alongside zinc finger nucleases and CRISPR/Cas9, TALEN is a prominent tool in the field of genome editing.
Increasing the number of zinc fingers increases the specificity by increasing the number of base pairs that the ZFN can bind to. [9] However too many zinc fingers can lead to off-target binding and thus offsite cleavage. [9] This is due to an increased likelihood of zinc fingers binding to parts of the genome outside of the gene of interest.
[254] [255] Clinical trials by Sangamo involving gene editing using zinc finger nuclease (ZFN) are ongoing. [256] In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published. Six of the seven patients on the high dose regime increased the level of the blood ...
Off-target genome editing refers to nonspecific and unintended genetic modifications that can arise through the use of engineered nuclease technologies such as: clustered, regularly interspaced, short palindromic repeats ()-Cas9, transcription activator-like effector nucleases (), meganucleases, and zinc finger nucleases (ZFN). [1]
Zinc finger protein chimera are chimeric proteins composed of a DNA-binding zinc finger protein domain and another domain through which the protein exerts its effect. The effector domain may be a transcriptional activator (A) or repressor (R), [1] a methylation domain (M) or a nuclease (N).
It has inspired research into other methods to try to block CCR5 expression through gene therapy. A procedure zinc-finger nuclease-based gene knockout has been used in a Phase I trial of 12 humans and led to an increase in CD4 count and decrease in their viral load while off antiretroviral treatment. [133] Attempt to reproduce this failed in 2016.