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Modulating gene expression to treat diseases

Published on December 13, 2021   20 min

Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms

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Hi, everybody. This is Navneet Matharu; I'm an Assistant Professor in the Department of Bioengineering and Therapeutic Sciences at UCSF. The topic of my talk today is future gene therapy strategies for modulating gene expression. It's my pleasure to discuss with you today some of the recent advances in research that highlight the use of non-editing versions of gene editors to treat genetic disorders.
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Broadly, there are three versions of gene editors that are explored in the last couple of decades first-generation: zinc-finger nucleases, second-generation: TALENs, and third-generation: the CRISPR system. All of these have programmable DNA recognition or targeting modules. Zinc finger nucleases have C2H2 zinc-finger domains for DNA recognition. TALENs have TAL effector DNA recognition and binding domains and CRISPR is a ribonuclease complex where DNA target recognition is guided by the guide, RNA. Zinc fingers or TALs can be made into nucleases by fusing the FOK1 restriction enzyme that creates a single-strand DNA break. It takes two zinc-finger FOK when fusion molecules to make a double-strand DNA break. CRISPR-Cas9 mind hazard to new peers domains that can make double-stranded DNA break. These editors can be programmed into nuclease deficient versions, for example, if you don't fuse a FOK1 to zinc-finger or TAL these molecules are nucleus deficient on their own. To make nuclease deficient CRISPR Cas9 we can mutate these two catalytically active nucleus domains such that it loses its DNA editing ability and we can make a dead Cas9 version out of it. Now, these DNA targeting modules can be fused to any effective domains that can perform a variety of biochemical functions at the target locus. These effector domains that can modulate the target gene expression are mostly transcription activators or repressors.

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Modulating gene expression to treat diseases

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