Abstract
Gene therapy is currently considered as the optimal treatment for inborn errors of metabolism (IEMs), as it aims to permanently compensate for the primary genetic defect. However, emerging gene editing approaches such as CRISPR‐Cas9, in which the DNA of the host organism is edited at a precise location, may have outperforming therapeutic potential. Gene editing strategies aim to correct the actual genetic mutation, while circumventing issues associated with conventional compensation gene therapy. Such strategies can also be repurposed to normalize gene expression changes that occur secondary to the genetic defect. Moreover, besides the genetic causes of IEMs, it is increasingly recognized that their clinical phenotypes are associated with epigenetic changes. Because epigenetic alterations are principally reversible, this may offer new opportunities for treatment of IEM patients. Here, we present an overview of the promises of epigenetics in eventually treating IEMs. We discuss the concepts of gene and epigenetic editing, and the advantages and disadvantages of current and upcoming gene‐based therapies for treatment of IEMs.
Highlights
A vector containing the correct coding DNA sequence of the defective gene is delivered into the host.[1]
Correction of the primary defects in inborn errors of metabolism (IEMs) would be preferred, the downsides of the available gene editing techniques stress the need for alternative therapeutic approaches
The DNA-binding protein (ZF/TALE) or the deactivated nuclease (“dead” Cas[9], or dCas[9], in case of clustered regularly interspaced short palindromic repeats (CRISPR)-[d]Cas9) serves as a “shuttle” protein to which other proteins can be fused, including artificial transcriptional activators, repressors, or otherfactors involved in expression regulation, that allow transient gene expression modulation (Figure 2)
Summary
KEYWORDS DNA methylation, (epi)genome editing, gene correction, histone modifications, inherited metabolic disease, therapy development A vector containing the correct coding DNA (cDNA) sequence of the defective gene is delivered into the host.[1] This method represents a compensation approach, as the endogenous genetic defect is not corrected.
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