Gene regulation is a complex and tightly controlled process that defines cell identity, health and disease, and response to pharmacologic and environmental signals. Recently developed DNA-targeting platforms, including zinc finger proteins, transcription activator-like effectors (TALEs) and the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system, have enabled the recruitment of transcriptional modulators and epigenome-modifying factors to any genomic site, leading to new insights into the function of epigenetic marks in gene expression. Additionally, custom transcriptional and epigenetic regulation is facilitating refined control over cell function and decision making. The unique properties of the CRISPR-Cas9 system have created new opportunities for high-throughput genetic screens and multiplexing targets to manipulate complex gene expression patterns. This Review summarizes recent technological developments in this area and their application to biomedical challenges. We also discuss remaining limitations and necessary future directions for this field.

/pdf/editing-the-epigenome-technologies-for-programmable-4ebmzfi6gx.pdf

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

Twenty-eight patients with advanced neovascular age-related macular degeneration (AMD) were given a single intravitreous injection of an E1-, partial E3-, E4-deleted adenoviral vector expressing human pigment epithelium- derived factor (AdPEDF.11). Doses ranging from 10(6) to 10(9.5) particle units (PU) were investigated. There were no serious adverse events related to AdPEDF.11 and no dose-limiting toxicities. Signs of mild, transient intraocular inflammation occurred in 25% of patients, but there was no severe inflammation. Six patients experienced increased intraocular pressure that was easily controlled by topical medication. All adenoviral cultures were negative. At 3 and 6 months after injection, 55 and 50%, respectively, of patients treated with 10(6)-10(7.5) PU and 94 and 71% of patients treated with 10(8)-10(9.5) PU had no change or improvement in lesion size from baseline. The median increase in lesion size at 6 and 12 months was 0.5 and 1.0 disk areas in the low-dose group compared with 0 and 0 disk areas in the high-dose group. These data suggest the possibility of antiangiogenic activity that may last for several months after a single intravitreous injection of doses greater than 10(8) PU of AdPEDF.11. This study provides evidence that adenoviral vector-mediated ocular gene transfer is a viable approach for the treatment of ocular disorders and that further studies investigating the efficacy of AdPEDF.11 in patients with neovascular AMD should be performed.

Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial.

We used a catheter-based technique to achieve generalized cardiac gene transfer in vivo and to alter cardiac function by overexpressing phospholamban (PL) which regulates the activity of the sarcoplasmic reticulum Ca 21 ATPase (SERCA2a). By using this approach, rat hearts were transduced in vivo with 5 3 10 9 pfu of recombinant adenoviral vectors carrying cDNA for either PL, b-galactosi- dase (b-gal), or modified green f luorescent protein (EGFP). Western blot analysis of ventricles obtained from rats trans- duced by Ad.PL showed a 2.8-fold increase in PL compared with hearts transduced by Ad.bgal. Two days after infection, rat hearts transduced with Ad.PL had lower peak left ven- tricular pressure (58.3 6 12.9 mmHg, n 5 8) compared with uninfected hearts (92.5 6 3.5 mmHg, n 5 6) or hearts infected with Ad.bgal (92.6 6 5.9 mmHg, n 5 6). Both peak rate of pressure rise and pressure fall (13, 210 6 298 mmHgys, 22, 117 6 178 mmHgys, n 5 8) were decreased in hearts overex- pressing PL compared with uninfected hearts (15, 225 6 136 mmHgys, 23, 805 6 97 mmHgys, n 5 6) or hearts infected with Ad.bgal (15, 108 6 167 mmHgys, 23, 765 6 121 mmHgys, n 5 6). The time constant of left ventricular relaxation increased significantly in hearts overexpressing PL (33.4 6 3.2 ms, n 5 8) compared with uninfected hearts (18.5 6 1.0 ms, n 5 6) or hearts infected with Ad.bgal (20.8 6 2.1 ms, n 5 6). These differences in ventricular function were maintained 7 days after infection. These studies open the prospect of using somatic gene transfer to modulate overall cardiac function in vivo for either experimental or therapeutic applications.

Modulation of ventricular function through gene transfer in vivo (sarcoplasmic reticulumyphospholambanycalciumyCa21 ATPaseyadenovirus)

pdf/microutrophin-delivery-through-raav6-increases-lifespan-and-33tbb74bgk.pdf

Microutrophin delivery through rAAV6 increases lifespan and improves muscle function in dystrophic dystrophin/utrophin-deficient mice.

The field of genome engineering has created new possibilities for gene therapy, including improved animal models of disease, engineered cell therapies, and in vivo gene repair. The most significant challenge for the clinical translation of genome engineering is the development of safe and effective delivery vehicles. A large body of work has applied genome engineering to genetic modification in vitro, and clinical trials have begun using cells modified by genome editing. Now, promising preclinical work is beginning to apply these tools in vivo. This article summarizes the development of genome engineering platforms, including meganucleases, zinc finger nucleases, TALENs, and CRISPR/Cas9, and their flexibility for precise genetic modifications. The prospects for the development of safe and effective viral and nonviral delivery vehicles for genome editing are reviewed, and promising advances in particular therapeutic applications are discussed.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-chembioeng-080615-034711

Engineering Delivery Vehicles for Genome Editing.

Gene Transfer of An Engineered Zinc Finger Protein Enhances the Anti-angiogenic Defense System

A Designed Zinc-finger Transcriptional Repressor of Phospholamban Improves Function of the Failing Heart

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Gene Transfer of An Engineered Zinc Finger Protein Enhances the Anti-angiogenic Defense System

A Designed Zinc-finger Transcriptional Repressor of Phospholamban Improves Function of the Failing Heart