TALEN gene editing takes aim on HIV

Abstract

Transcription activator-like effector nucleases (TALENs) are one of several types of programmable, engineered nucleases that bind and cleave specific DNA sequences. Cellular machinery repairs the cleaved DNA by introducing indels. In this review, we emphasize the potential, explore progress, and identify challenges in using TALENs as a therapeutic tool to treat HIV infection. TALENs have less off-target editing and can be more effective at tolerating HIV escape mutations than CRISPR/Cas-9. Scientists have explored TALEN-mediated editing of host genes such as viral entry receptors (CCR5 and CXCR4), and a protein involved in proviral integration (LEDGF/p75). Viral targets include the proviral DNA, particularly, and the long terminal repeats. Major challenges with translating gene therapy from bench to bedside are improving cleavage efficiency and delivery, while minimizing off-target editing, cytotoxicity, and immunogenicity. However, rapid improvements in TALEN technology are enhancing cleavage efficiency and specificity. Therapeutic testing in animal models of HIV infection will help determine whether TALENs are a viable HIV treatment therapy. TALENs or other engineered nucleases could shift the therapeutic paradigm from life-long antiretroviral therapy towards eradication of HIV infection.

Genetic Strategies for HIV Treatment and Prevention

“…Cytokines and antibody derivatives with endoplasmic reticulum retention signal (intrakines and intrabodies, respectively) were designed to retain CCR5 inside gene-modified cells. 8 , 9 , 10 , 11 Ribozymes and small hairpin RNAs (shRNAs) have been utilized to target CCR5 mRNA, 12 , 13 , 14 , 15 while genome-editing enzymes, such as zinc-finger nucleases (ZFNs), 16 , 17 transcription activator-like effector nucleases (TALENs), 18 , 19 and CRISPR-associated protein-9 nuclease (Cas9) have been employed to introduce mutations into the CCR5 gene. 20 , 21 , 22 …”

Novel AIDS therapies based on gene editing

“…Targets for TALEN that have been exploited against HIV-1 include the provirus and cellular genes required for HIV infection such as the CCR5 coreceptor and lens epithelium-derived growth factor, LEDGF/p75 [62]. Some studies suggest that TALEN have the advantages that they have low cellular toxicity and off-target effects and are able to target methylated DNA, which is relevant to targeting latent HIV-1 provirus [62]. In addition, they are monomers with degenerate recognition sites that are able to target predicted escape mutations [63], which that will be discussed subsequently.…”

“…Disadvantages are that TALENs take longer to construct compared to CRISPR, where you only need to make new gRNA. In addition, TALENs are larger and hence are more difficult to deliver [62]. Ru et al [64] used a cell-penetrating peptide-based system for TALEN delivery by constructing a functional Tat-TALEN proteins with cell-penetrating HIV-1 Tat peptide fused to TALEN.…”

To Crispr And Beyond: The Evolution Of Genome Editing In Stem Cells

“…TALENs-mediated gene correction has been demonstrated in fibroblasts derived from epidermolysis bullosa patients [63]. Additionally, numerous studies have used TALENs on human pluripotent stem cells for development of targeted gene therapy [64][65][66][67].…”