Gene Therapy Strategies: Gene Silencing

Abstract

It was already mentioned throughout this book that gene therapy was primarily developed as a strategy targeting recessive monogenic disorders caused by non-functional mutant genes, where in theory the simple addition of a functional (non-mutated) copy of the causative gene would be enough to counteract the disease phenotype and cure the disease. Nevertheless, for more complex diseases, the addition of a normal gene is not enough to revert the disease phenotype. For example, in dominantly inherited disorders, the presence of a single abnormal allele is sufficient to lead to disease manifestation, and thus a gene therapy should instead be able to shut down (or silence) the expression of that abnormal gene. Although this strategy is not so linear and easy, the possibility of silencing the expression of mutant genes using gene therapy approaches became possible with the development of antisense oligonucleotides (ASOs) and with the discovery of the RNA interference (RNAi) pathway. Despite several differences that will be explored further in this chapter, gene therapy strategies based on these two tools have been demonstrated to be efficient in treating dominant genetic diseases. More recently, gene editing tools have also been used to perform gene silencing, including at the DNA level, for example by introducing a premature stop codon or by removing the defective gene; however, this and other gene editing approaches will be discussed in Chap. 8.