Therapeutic Editing of the TP53 Gene: Is CRISPR/Cas9 an Option?

Abstract

The TP53 gene encodes the transcription factor and oncosuppressor p53 protein that regulates a multitude of intracellular metabolic pathways involved in DNA damage repair, cell cycle arrest, apoptosis, and senescence. In many cases, alterations (e.g., mutations of the TP53 gene) negatively affect these pathways resulting in tumor development. Recent advances in genome manipulation technologies, CRISPR/Cas9, in particular, brought us closer to therapeutic gene editing for the treatment of cancer and hereditary diseases. Genome-editing therapies for blood disorders, blindness, and cancer are currently being evaluated in clinical trials. Eventually CRISPR/Cas9 technology is expected to target TP53 as the most mutated gene in all types of cancers. A majority of TP53 mutations are missense which brings immense opportunities for the CRISPR/Cas9 system that has been successfully used for correcting single nucleotides in various models, both in vitro and in vivo. In this review, we highlight the recent clinical applications of CRISPR/Cas9 technology for therapeutic genome editing and discuss its perspectives for editing TP53 and regulating transcription of p53 pathway genes.

Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy

“…CRIPSR/Cas9 gene editing, including Base Editing, Prime Editing and upcoming technologies have set a high expectations bar for future clinical applications ( Figure 2C ). BEs, PEs and similar approaches that allow introduction of precise genetic corrections into a target locus without deleting the whole gene could potentially be used to correct TP53 missense mutations as a prospective anticancer therapy ( 59 ). Given the rapid advancement of CRISPR/Cas9 technologies and their inevitable introduction to clinical practice, both ex vivo and in vivo target gene modifications in a wide range of cancers, including solid tumors, does not seem to be a distant future anymore.…”

Promising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies

“…The APCs can be programmed for expression of pMHC using vector-based approaches (62,63) or modern CRISPR-based genome-editing techniques (64,65). Off-target toxicity issues may be resolved by testing in humanized animal models or using cell reprogramming tools to generate different types of tissues for using them as antigen-bearing surrogates or organoids (66).…”

TP53 in Myelodysplastic Syndromes

“…CRISPR/Cas can potentially target the entire mutated TP53 locus, replace it with a functional cDNA copy of TP53 by homologous recombination, or target various hotspot mutations in a more precise way, leading to a single nucleotide substitution or precise gene editing [ 87 ]. CRISPR/Cas9 gene-editing therapies for the treatment of hematological diseases including sickle cell disease, β-Thalassemia, leukemia, lymphoma, and multiple myeloma have been tested in clinical trials, and recent results indicate that one patient with sickle cell disease and two patients with thalassemia no longer required blood transfusions [ 88 ]. No data for this technique for treating MDS has been reported till now.…”

“…The inherent functions of wild-type TP53 for DNA damage repair may affect the efficacy of CRISPR/Cas9 gene edition. A deeper understanding of the impact of TP53 status on the efficacy of CRISPR/Cas9 machinery will facilitate the development of gene-editing therapies [ 88 ]. The CRISPR/Cas targeting therapeutic system continues to evolve to improve accuracy and reduce off-target or side effects.…”