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Regulatory Changes and Partnerships will Enable Gene Editing Technologies as a Platform-based Therapeutic Approach

CRISPR Cas9-mediated Genomic Editing

It has long been postulated that the genetic code containing the instructions for life could be precisely edited to correct and cure human disease. That dream began the transition towards reality with the breakthrough 2012 publication that first demonstrated use of the CRISPR-Cas9 endonuclease system.1 Since then, CRISPR-Cas-based genome editing technologies have changed virtually every facet of basic and applied biological research, holding the potential to push both medicine and science into an age of innovation unlike any seen previously.

The CRISPR-Cas9 effector nuclease, from a class 2 bacterial CRISPR system, consists of a small guide RNA (sgRNA) and the Cas endonuclease.1,2 By modifying and controlling the nucleotide sequence of the guide RNA, the artificial Cas9 system could be programmed to target virtually any DNA sequence. Thus, by utilising the CRISPR-Cas9 system, delivered to a host cell either through viral or nonviral mechanisms, distinct insertions, deletions, or point mutations can be introduced at any loci of interest in the host genome through DNA repair mechanisms.3

The Clinical Promise of CRISPR-Cas9 Based Gene Editing

Given the power and utility of CRISPR-Cas9-based genomic editing, it has been utilised extensively in basic as well as translational research to better understand gene function and to ultimately explore clinical targets. Studies utilising both in vitro as well as in vivo experimental models have generated compelling and promising results against a vast list of target disease indications.

In the context of cancer, CRISPR-mediated knockouts of genes essential for the regulation of the cell cycle and drug resistance have been performed to modulate disease.4,5 In other studies involving neurological disorders such as Huntington’s and Alzheimer’s Disease, CRISPR-Cas9-mediated editing was used to suppress the pathogenic expansion of the HTT gene or correct a pathogenic allele of the presenilin 1 gene (PSEN1), respectively.6,7 Other research areas such as immunology, cardiology, and hematology have all benefited from the application of CRISPR in preclinical models.

Cumulatively, the experimental evidence from preclinical studies suggests that successful genome editing can be accomplished using the CRISPR-Cas9 system, which has in turn facilitated translation and clinical evaluation of this technology.8 As a result, clinical trials utilising CRISPR technology have exploded with both ex vivo and in vivo gene editing approaches being explored in multiple therapeutic areas.9

Complex Biology and Regulatory Systems Favor Safe Plays

Historical guiding principles in drug development have focused on the underlying pathogenic mechanisms of disease and how to target the biological process to bring forth a favourable clinical outcome. One significant limitation to this approach is that the etiology of a disease can arise from multiple, diverse, and in many instances, multi-faceted underlying biological mechanisms that are impossible to co-target in today’s developmental and regulatory framework.