Genome and Epigenome Editing to Treat Disorders of the Hematopoietic System

Abstract

The possibility of editing complex genomes in a targeted fashion has revolutionized basic research as well as biomedical and biotechnological applications in the last 5 years. The targeted introduction of genetic changes has allowed researchers to create smart model systems for basic research, bio-engineers to modify crops and farm animals, and translational scientists to develop novel treatment approaches for inherited and acquired disorders for which curative treatment options are not yet available. With the rapid development of genome editing tools, in particular zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR-Cas system, a wide range of therapeutic options have been-and will be-developed at an unprecedented speed, which will change the clinical routine of various disciplines in a revolutionary way. This review summarizes the fundamentals of genome editing and the current state of research. It particularly focuses on the advances made in employing engineered nucleases in hematopoietic stem cells for the treatment of primary immunodeficiencies and hemoglobinopathies, provides a perspective of combining gene editing with the chimeric antigen receptor T cell technology, and concludes by presenting targeted epigenome editing as a novel potential treatment option.

PSMA-Directed CAR T Cells Combined with Low-Dose Docetaxel Treatment Induce Tumor Regression in a Prostate Cancer Xenograft Model

“…It will be interesting to assess whether DTX treatment induces the secretion of CD8 + T cell-attracting cytokines from prostate cancer cells, as previously reported for non-small-cell lung cancer. 32 Furthermore, it will be attractive to combine DTX treatment with “enhanced” CAR T cells 43 , 44 by knocking out, for example, genes coding for inhibitory receptors, such as PD-1, 45 CTLA4, 46 LAG3, 47 or the T cell receptor, 48 or to introduce simple modifications to the CAR scaffold that have proven to increase safety and efficacy of CAR T cells in preclinical models of leukemia and lymphoma. 34 , 35 …”

Genome Editing for Mucopolysaccharidoses

“…Advantages of the ex vivo approach include the control over which cells are targeted and the ability to fully characterize the editing outcomes, both intended (on-target) and unintended (off-target), in the targeted population. This approach has been extensively used in the hematopoietic system, where the isolation, culture, and transplantation of these cells is now routine [35,36]. However, not all organ functions can be replaced by transplantation of genome edited cells modified ex vivo.…”

“…Ideal candidate cells for ex vivo modification are tissue-specific stem cells. Among these, hematopoietic stem and progenitor cells have been heavily studied as clinicians and researchers have extensive experience with their isolation, ex vivo manipulation, and transplantation [35,36]. Furthermore, hematopoietic stem cell transplantation (HSCT) in the allogenic setting has been shown to be a feasible enzyme reservoir in several metabolic disorders and MPSs [87][88][89].…”

Genome editing and selection based on genes associated with sports athletic performance

“…They can activate the inactive genes or inactivate the genes that are active in specific cells. Thus far, these technologies were used in studies aiming to treat different genetic diseases such as Barth syndrome, Duchenne muscular dystrophy, hemophilia, β-thalassemia, chronic inflammatory lung diseases, and even Huntingtonʼs disease (Mussolino et al, 2017(Mussolino et al, :1105(Mussolino et al, -1115Thakore et al, 2016:127-137;Song et al, 2017:L334-L347). In the field of biomedicine, it works in a way that after the discovery of a gene aberration and its association with the disease, the CRISPR/Cas9 method could be used to reverse that aberration and treat specific disease by treating its cause.…”