Genetic Disorder Therapeutics



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Genetic Disorder Therapeutics

Genetic disorder is a disease caused in whole or in part by a change in the DNA sequence away from the normal sequence. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Most genetic disorders cannot be cured or even ameliorated using conventional methods of treatment. RNA targeting is emerging as a powerful alternative to conventional therapies for the treatment of genetic disorders.

Although an emerging field, RNA-target therapeutics has the potential to circumvent some of the shortcomings of standard gene therapy methods, including low efficiency, limitation of transgene size, insertional mutagenesis, and integration-associated events. Moreover, some disease situations could be more amenable to correction by RNA targeting, such as autosomal dominant diseases, where introduction of a functional gene does not address expression of the dominant mutant transcript.

There are five RNA-based approaches to treat genetic disorders:

  • ASO-mediated exon skipping

An antisense oligonucleotide (ASO) is a synthesized short nucleic acid polymer, typically fifty or fewer base pairs in length that will bind to the mutation site in the pre-mRNA, to induce exon skipping, then result in an internally deleted protein (Figure 1). ASO-mediated splicing modulation is currently in clinical trials for Duchenne muscular dystrophy and spinal muscular atrophy, and in preclinical stages for several other genetic conditions.

  • RNA trans-splicing

In recent years, spliceosome-mediated RNA trans-splicing (SMaRT) has emerged as an attractive option for the repair of mutations on the mRNA level. SMaRT uses the cellular splicing machinery to recombine an endogenous target pre-mRNA containing a mutation with an exogenously delivered pre-mRNA trans-splicing molecule coding for part of the wild-type transcript (Figure1). After successful recombination, a hybrid full-length wild-type mRNA is generated, and wild-type protein synthesis restored. This method has been demonstrated in cell and animal models for a variety of human genetic diseases including Alzheimer's disease, Alzheimer's disease, haemophilia A, cystic fibrosis and retinitis pigmentosa.

  • Transcript replacement

Transcript replacement therapy introduces mRNA transcripts into cells to drive synthesis of wild-type proteins. In situ production of a protein in cells that naturally express this protein guarantees correct post-translational modification, which helps overcome concerns about reduced functionality and immunogenicity of recombinant proteins. However, transcript replacement therapy is still in its infancy due to the low transfection efficiency.

  • IVT mRNA-mediated genome editing

To permanently correct a gene, an IVT mRNA encoding such site-specific nucleases can be provided to cells together with a DNA template. After double-stranded breaks created by the nuclease, which is encoded by the IVT mRNA, the DNA template may be inserted between the breaks during repair by homologous recombination. The outcome of this approach is correction of the mutated gene and restoration of wild-type protein synthesis.

  • Mutant gene/allele knockdown

siRNA and ASO can be utilized to knock down mutant mRNA transcripts. The two methods constitute particularly interesting therapeutic options for dominantly inherited diseases.

RNA-based therapy approaches for genetic disordersFigure1. RNA-based therapy approaches for genetic disorders

The goal of the IntegrateRNA is to support basic and applied research in RNA biology to generate novel insights into the role of RNA in health and disease and provide new tools and targets for RNA research, diagnostics and therapies. For further information, please feel free to contact us.


  1. Bornert O. et al. RNA-based therapies for genodermatoses. Experimental Dermatology, 2017.
  2. Connor P. et al. Genetic medicines: treatment strategies for hereditary disorders. Nature Reviews Genetics, 2006, 7(4):261-276.
For research use only. Not intended for any clinical use.
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