Genetic factors contribute to most categories of human disease, including those that are inherited, infectious and malignant. It has therefore been a long-standing goal of biomedical science to develop a means to modify genomes within patients to correct disease-causing mutations, disable the genomes of invading pathogens, arm immune cells to attack tumours and enable countless other therapeutic opportunities. In some instances, gene addition can have therapeutic value, and gene therapy—the field that develops this approach—is experiencing ever-increasing success. In many other cases, however, the genome of the patient must be edited to achieve therapeutic benefit. Genome editing broadly encompasses diverse technologies that can make many different genomic alterations in different contexts, and the topic has been the subject of recent and comprehensive reviews. Several concepts in genome editing (Fig.) are central to the goals and strategies of the SCGE Consortium, which we describe in this Perspective.
Fig: Tools for editing the genomes of cells within the body
Over the past few decades, a steady progression of techniques and technologies that enable user-programmable genome editing has been introduced, tested, improved and implemented. These include homologous recombination, zinc-finger nucleases (ZFNs), meganucleases and transcription activator-like effector nucleases (TALENs). Most recently, engineered molecular machinery derived from bacterial immune pathways—known as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins (CRISPR–Cas systems) have revolutionized genome editing, in part because their target sequences can be simply programmed with easily designed RNA guides. Despite these promising advances, challenges remain before the transformative potential of therapeutic genome editing can be fully realized. Here we outline the goals and strategies of the SCGE Consortium, which has been established by the United States NIH to accelerate the development of solutions to many of these challenges. The NIH has allocated around US$190 million over 6 years in support of the SCGE Consortium, which now includes 72 principal investigators from 38 institutions that are pursuing 45 distinct but well-integrated projects.
Genome editing of somatic cells can be carried out either ex vivo, followed by the re-introduction of edited cells into the patient, or in vivo, by delivering the editing machinery to tissues within the body. An important distinction is the editing of somatic tissues versus germline tissues: the latter has the potential to transmit genetic changes to future generations. The SCGE Consortium is strictly focused on somatic editing; germline editing is not only excluded as a goal but is also considered to be an unacceptable outcome that should be carefully prevented.
Saha, K., Sontheimer, E.J., Brooks, P.J. et al. The NIH Somatic Cell Genome Editing program. Nature 592, 195–204 (2021). https://doi.org/10.1038/s41586-021-03191-1