How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

Myriam Sainz-Ramos,Jon Zarate,Idoia Gallego,Gustavo Puras,Jose Luis Pedraz,Ilia Villate-Beitia,Iván Maldonado

doi:10.3390/ijms22147545

Abstract

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

Highlights

The main concept of gene therapy is quite simple and overall relies on the delivery of exogenous genetic material into target cells to modulate the expression of an altered genome
The nanometric particle size of non-viral vectors should be reported as hydrodynamic diameter by cumulative analysis [90] rather than by the area of the predominant peak measured by dynamic light scattering (DLS), normally in a Zetasizer instrument
The substantial progress that has been achieved during the past years in different research areas associated with the design of novel gene delivery systems, along with the gain of knowledge acquired in genomics and structural biology, has raised reasonable hope to consider the regular application into medical practice of non-viral vectors as gene delivery systems to face many devastating diseases

Summary

Introduction

The main concept of gene therapy is quite simple and overall relies on the delivery of exogenous genetic material into target cells to modulate the expression of an altered genome. In the case of gene addition therapy, a “healthy” copy of the gene is administered to recover the functionality of the affected cells This strategy can be suitable to face diseases caused by mutations with loss of function [1]. In the case of a mutation that overexpresses genes, the aim is to administer an inhibitory sequence to knock out the expression of the mutated gene [3] This strategy is referred to as gene inhibition therapy and can be applied, for instance, to face autosomal dominant retinitis pigmentosa secondary to specific mutations in the pre-mRNA splicing-factor gene PRPF31 [4]. The third approach, named as genome editing, incorporates specific genome editing tools to repair mutations in the genome with gain or loss of function [5] This strategy has been successfully used in combination with iPSC technologies to combat human β-thalassemia disease in mice [6]

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