Abstract
Many genetic diseases and undesirable traits are due to base-pair alterations in genomic DNA. Base-editing, the newest evolution of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas-based technologies, can directly install point-mutations in cellular DNA without inducing a double-strand DNA break (DSB). Two classes of DNA base-editors have been described thus far, cytosine base-editors (CBEs) and adenine base-editors (ABEs). Recently, prime-editing (PE) has further expanded the CRISPR-base-edit toolkit to all twelve possible transition and transversion mutations, as well as small insertion or deletion mutations. Safe and efficient delivery of editing systems to target cells is one of the most paramount and challenging components for the therapeutic success of BEs. Due to its broad tropism, well-studied serotypes, and reduced immunogenicity, adeno-associated vector (AAV) has emerged as the leading platform for viral delivery of genome editing agents, including DNA-base-editors. In this review, we describe the development of various base-editors, assess their technical advantages and limitations, and discuss their therapeutic potential to treat debilitating human diseases.
Highlights
The recent discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system has revolutionized the field of molecular biology and medicine [1]
CRISPR-mediated genome editing involves the generation of a Cas9-induced double-strand break that is repaired by non-homologous end joining (NHEJ) mechanisms or by homology directed repair (HDR) [2,3,4]
HDR can be harnessed to insert a specific DNA template for precise restoration of the DNA sequence, this pathway is characterized by limited efficiency and high rates of undesired insertion or deletion mutations that nullify the potential benefit from repairing the mutation [5,6]
Summary
The recent discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas system has revolutionized the field of molecular biology and medicine [1]. DNA base-editing and prime-editing has remarkable potential as a therapeutic tool to correct disease-causing mutations in the human genome. DNA base-editing and prime-editing may prove to be well adapted for correction of large genes, where the vector-mediated delivery of the target gene is not feasible due to the limited packaging capacity of viral vectors [11]. Development of safe and efficient delivery systems is crucial for the success of CRISPR-Cas base-editing and prime-editing in the clinic [14,15]. We review the CRISPR/Cas base-editing toolkit, describe the adeno-associated vector as a delivery vehicle for BE-mediated gene therapy, and discuss their therapeutic potential to treat inherited human diseases
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