Abstract
DNA transposons are primitive genetic elements which have colonized living organisms from plants to bacteria and mammals. Through evolution such parasitic elements have shaped their host genomes by replicating and relocating between chromosomal loci in processes catalyzed by the transposase proteins encoded by the elements themselves. DNA transposable elements are constantly adapting to life in the genome, and self-suppressive regulation as well as defensive host mechanisms may assist in buffering ‘cut-and-paste’ DNA mobilization until accumulating mutations will eventually restrict events of transposition. With the reconstructed Sleeping Beauty DNA transposon as a powerful engine, a growing list of transposable elements with activity in human cells have moved into biomedical experimentation and preclinical therapy as versatile vehicles for delivery and genomic insertion of transgenes. In this review, we aim to link the mechanisms that drive transposon evolution with the realities and potential challenges we are facing when adapting DNA transposons for gene transfer. We argue that DNA transposon-derived vectors may carry inherent, and potentially limiting, traits of their mother elements. By understanding in detail the evolutionary journey of transposons, from host colonization to element multiplication and inactivation, we may better exploit the potential of distinct transposable elements. Hence, parallel efforts to investigate and develop distinct, but potent, transposon-based vector systems will benefit the broad applications of gene transfer. Insight and clever optimization have shaped new DNA transposon vectors, which recently debuted in the first DNA transposon-based clinical trial. Learning from an evolutionary drive may help us create gene vehicles that are safer, more efficient, and less prone for suppression and inactivation.
Highlights
Since its birth the field of therapeutic gene transfer has travelled on a rough road from initial optimism through hype and disappointment towards scientifically wellfounded hope and signs of clinical applicability and success
Mobile elements heading for the clinic Fifteen years have gone since the Sleeping Beauty element was re-awakened and soon after adapted for in vivo gene delivery facilitating persistent gene expression
Despite the various examples of pre-clinical efficacy for DNA transposon-based in vivo gene therapy, the road to the clinic will wind through additional experimentation and evidence of therapeutic effects in large animal models
Summary
Since its birth the field of therapeutic gene transfer has travelled on a rough road from initial optimism through hype and disappointment towards scientifically wellfounded hope and signs of clinical applicability and success. The simple gene integration machinery of cut-and-paste transposons provides non-viral gene delivery systems – naked plasmid-based DNA vectors as the most primitive system – with the ability to insert transgenes into target cell genomes. The mobility of nucleic acid sequences in discrete genetic segments has incredible impact on the dynamics and evolution of almost any genome Driving their survival, transposable elements possess a unique ability to multiply within genomes, leading to an abundance of genetic entities with no obvious beneficial effects on the host. DNA transposable elements that move around the genome by a cut-and-paste mechanism are usually shorter than retrotransposable elements, typically in the range from 1 to 5 kb, and have terminal inverted repeats (IRs) that contain binding sites for the transposase, which is often the only protein encoded by the transposon. These atypical elements transpose by a replicative mechanism that they share with circular ssDNA bacteriophages, bacterial plasmids, and geminiviruses
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