Abstract
Genome editing technologies, particularly those based on zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR (clustered regularly interspaced short palindromic repeat DNA sequences)/Cas9 are rapidly progressing into clinical trials. Most clinical use of CRISPR to date has focused on ex vivo gene editing of cells followed by their re-introduction back into the patient. The ex vivo editing approach is highly effective for many disease states, including cancers and sickle cell disease, but ideally genome editing would also be applied to diseases which require cell modification in vivo. However, in vivo use of CRISPR technologies can be confounded by problems such as off-target editing, inefficient or off-target delivery, and stimulation of counterproductive immune responses. Current research addressing these issues may provide new opportunities for use of CRISPR in the clinical space. In this review, we examine the current status and scientific basis of clinical trials featuring ZFNs, TALENs, and CRISPR-based genome editing, the known limitations of CRISPR use in humans, and the rapidly developing CRISPR engineering space that should lay the groundwork for further translation to clinical application.
Highlights
Recent advances in biotechnology have revolutionized our ability to understand the genetic basis of human health
Similar to the studies in X-linked severe combined immunodeficiency (SCID-X1), genome editing followed by integration of provided sequence to insert functional gene copy has been demonstrated in chronic granulomatous disease (CGD) patient cells and resulted in long-term engraftment in immunodeficient mice using transcription activator-like effector nuclease (TALEN) [108], zinc-finger nuclease (ZFN) [107,108,110], and Cas9 [106,109], laying the groundwork for clinical trials in this space
The first is the use of Cas9 to correct the E50-MD canine model of Duchenne muscular dystrophy (DMD), the present study examined both localized muscle delivery and systemic delivery via associated virus (AAV)
Summary
Recent advances in biotechnology have revolutionized our ability to understand the genetic basis of human health. Pre-clinical studies in SCID-X1 have focused on addition of a functional copy of interleukin-2 receptor subunit γ (IL2RG) into the AAV1 safe harbor site or, more commonly, into native gene site [103,104,105] These studies were able to demonstrate functional gene expression and long-term engraftment in immunodeficient mouse models utilizing ZFNs [103,105] and Cas9 [104] genome editing followed by integration of the provided therapeutic gene copy in SCID-X1 patient cells. Similar to the studies in SCID-X1, genome editing followed by integration of provided sequence to insert functional gene copy has been demonstrated in CGD patient cells and resulted in long-term engraftment in immunodeficient mice using TALENs [108], ZFNs [107,108,110], and Cas9 [106,109], laying the groundwork for clinical trials in this space. The potential to selectively silence a mutated gene or activate the healthy gene copy with long duration effects has vast potential in medicine that could be achieved as CRISPR epigenome editing technology advances
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