![]() However, this was followed by some major setbacks. While one patient showed moderate improvement, the other did not ( 5, 6) Although initial results were suboptimal, the early evidence of feasibility prompted multiple subsequent gene therapy trials using viral-mediated gene edition. Two young girls with ADA-SCID were treated with retroviruses for ex vivo delivery of a wildtype adenosine deaminase gene to autologous T-lymphocytes, which were then infused back into the patients ( 5, 6). Soon after, the first clinical trial that used gene therapy for therapeutic intent was approved in 1990 for the monogenic disease adenosine deaminase-severe combined immunodeficiency (ADA-SCID). ![]() Although the neomycin tagging of TILs did not have a direct therapeutic intent and was used for tracking purposes, this study was the first to provide evidence for both the feasibility and safety of viral-mediated gene therapy. ![]() One of these pioneering clinical trials involved ex vivo retroviral delivery of a selective neomycin-resistance marker to tumor infiltrating leukocytes (TILs) extracted from advanced melanoma patients ( 4). Initially, gene therapy utilized viral vector delivery of therapeutic transgenes for cancer treatment ( 2) or monogenic disease ( 3). The introduction of gene therapy into the clinic provided hope for thousands of patients with genetic diseases and limited treatment options. This review aims to (1) provide a brief history of gene therapy prior to CRISPR and discuss its ethical dilemmas, (2) describe the mechanisms by which CRISPR/Cas9 induces gene edits, (3) discuss the current limitations and advancements made for CRISPR technology for therapeutic translation, and (4) highlight a few recent clinical trials utilizing CRISPR gene therapy while opening a discussion for the ethical barriers that these and future trials may hinge upon. However, there are several technical and ethical considerations that need addressing when considering its use for patient care. The recent advent of CRISPR technology in clinical trials has paved way for the new era of CRISPR gene therapy to emerge. The discovery and development of the CRISPR/Cas9 system has provided a second opportunity for gene therapy to recover from its stigma and prove to be valuable therapeutic strategy. Gene therapy has witnessed both early successes and tragic failures in a clinical setting. Gene therapy as a strategy to provide therapeutic benefit includes modifying genes via disruption, correction, or replacement ( 1). We review the emerging data of recent gene therapy trials and consider the best strategy to move forward with this powerful but still relatively new technology. This review focuses on the evolution of gene therapy and the role of CRISPR in shifting the gene therapy paradigm. Although it has apparent advantages, CRISPR/Cas9 brings its own set of limitations which must be addressed for safe and efficient clinical translation. While viral vectors remain a key delivery vehicle, CRISPR technology provides a relatively simple and efficient alternative for site-specific gene editing, obliviating some concerns raised by traditional gene therapy. Traditional gene therapy has raised some concerns, as its reliance on viral vector delivery of therapeutic transgenes can cause both insertional oncogenesis and immunogenic toxicity. The discovery of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated (Cas) proteins has expanded the applications of genetic research in thousands of laboratories across the globe and is redefining our approach to gene therapy. A series of recent discoveries harnessing the adaptive immune system of prokaryotes to perform targeted genome editing is having a transformative influence across the biological sciences.
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