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Review
. 2020 Jan;43(1):63-70.
doi: 10.1002/jimd.12093. Epub 2019 Apr 22.

Exploiting epigenetics for the treatment of inborn errors of metabolism

Affiliations
Review

Exploiting epigenetics for the treatment of inborn errors of metabolism

Martijn G S Rutten et al. J Inherit Metab Dis. 2020 Jan.

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.

Keywords: (epi)genome editing; DNA methylation; gene correction; histone modifications; inherited metabolic disease; therapy development.

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Conflict of interest statement

The authors declare no potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic overview of the three main gene editing tools. A, Zinc finger nuclease (ZFN), consisting of a DNA‐cutting nuclease domain (gray box), and a protein‐based DNA‐binding domain of three zinc finger proteins (colored circles), each recognizing a three base pairs (bp) DNA sequence. Hence, this ZFN recognizes a 9 bp genomic sequence. B, Transcription‐activator like effector nuclease (TALEN), consisting of a DNA‐cutting nuclease domain (gray box), and a protein‐based DNA‐binding domain of 18 TAL effector repeats. Each TAL effector consists of 34 amino acids, typically highly conserved, with positions 12 and 13 being variable and determining the specific recognition of one DNA bp. Hence, this TALEN recognizes a 18 bp genomic sequence. C, Clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 system, consisting of a DNA‐cutting nuclease (gray box), with two sites of nuclease activity, and a RNA‐based DNA‐binding domain consisting of a single guide RNA (sgRNA), with the variable 20 nucleotide RNA‐sequence determining recognition of a 20 bp complementary genomic sequence
Figure 2
Figure 2
Comparison of different strategies to treat IEMs. A, Conventional gene therapy, based on the introduction of a cDNA or mRNA sequence encoding a correct version of the mutated gene. As a result, the defect is compensated without altering the genomic sequence of the host. B, Gene editing using (in this case) CRISPR‐Cas9, which aims to correct the mutated gene by altering the genomic sequence of the host at a precise location, or which can be used to modify the expression of proteins that compensate for the genetic defect via alterations in the genome. C, Epigenetic editing using an epigenetic writer or erasers fused to (in this case) the CRISPR‐dCas9 system to compensate for the genetic defect, for example, by increasing the residual expression of a mutated protein to enhance its activity, or by modifying the expression of proteins capable of compensating for the genetic defect, via gene‐specific alterations in the epigenetic landscape

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