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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.
The zinc finger nucleases that have been synthesized for this treatment are manufactured by combining FokI Type II restriction endonucleases with engineered zinc fingers. [9] [12] The number of zinc fingers attached to the endonuclease controls the specificity of the ZFN since they are engineered to preferentially bind to specific base ...
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.
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.
Early techniques randomly inserted the genes into the genome. Advances allow targeting specific locations, which reduces unintended side effects. Early techniques relied on meganucleases and zinc finger nucleases. Since 2009 more accurate and easier systems to implement have been developed.
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).