Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs)

Autoren

Kerstin Nagel-Wolfrum
Fabian Möller
Inessa Penner
Timor Baasov
Uwe Wolfrum

DOI

10.1007/s40259-016-0157-6

eISSN

1179-190X

ISSN

1173-8804

Ausgabe der Veröffentlichung

2

Zeitschrift

BioDrugs

Sprache

en

Online publication date

2016

Paginierung

49 - 74

Datum der Veröffentlichung

2016

Status

Published

Herausgeber

Springer Science and Business Media LLC

Herausgeber URL

http://dx.doi.org/10.1007/s40259-016-0157-6

Datum der Datenerfassung

2022

Titel

Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs)

Ausgabe der Zeitschrift

30

Data source: Crossref

Abstract

In recent years, remarkable advances in the ability to diagnose genetic disorders have been made. The identification of disease-causing genes allows the development of gene-specific therapies with the ultimate goal to develop personalized medicines for each patient according to their own specific genetic defect. In-depth genotyping of many different genes has revealed that ~12% of inherited genetic disorders are caused by in-frame nonsense mutations. Nonsense (non-coding) mutations are caused by point mutations, which generate premature termination codons (PTCs) that cause premature translational termination of the mRNA, and subsequently inhibit normal full-length protein expression. Recently, a gene-based therapeutic approach for genetic diseases caused by nonsense mutations has emerged, namely the so-called translational read-through (TR) therapy. Read-through therapy is based on the discovery that small molecules, known as TR-inducing drugs (TRIDs), allow the translation machinery to suppress a nonsense codon, elongate the nascent peptide chain, and consequently result in the synthesis of full-length protein. Several TRIDs are currently under investigation and research has been performed on several genetic disorders caused by nonsense mutations over the years. These findings have raised hope for the usage of TR therapy as a gene-based pharmacogenetic therapy for nonsense mutations in various genes responsible for a variety of genetic diseases.

Addresses

Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg-University of Mainz, Johannes-von-Mueller-Weg 6, 55099, Mainz, Germany. nagelwol@uni-mainz.de.

Autoren

Kerstin Nagel-Wolfrum
Fabian Möller
Inessa Penner
Timor Baasov
Uwe Wolfrum

DOI

10.1007/s40259-016-0157-6

eISSN

1179-190X

Externe Identifier

PubMed Identifier: 26886021

Funding acknowledgements

Foundation Fighting Blindness (FFB), U.S.A.: TA-NMT-0611-0538-JGU
European Community: FP7/2009/241955 (SYSCILIA)
Deutsche Forschungsgemeinschaft (DE): GRK 1044
FAUN-Stiftung, Nuremberg:
Tistou & Charlotte Kerstan Stiftung:
BMBF: BMBF under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases"

Open access

false

ISSN

1173-8804

Ausgabe der Veröffentlichung

2

Zeitschrift

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

Schlüsselwörter

Animals
Humans
Genetic Diseases, Inborn
RNA, Messenger
Codon, Nonsense
Pharmaceutical Preparations
Genotype
Genetic Therapy

Sprache

eng

Medium

Print

Paginierung

49 - 74

Datum der Veröffentlichung

2016

Status

Published

Datum der Datenerfassung

2016

Titel

Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs).

Sub types

Research Support, Non-U.S. Gov't
Review
Journal Article

Ausgabe der Zeitschrift

30

Data source: Europe PubMed Central

Abstract

In recent years, remarkable advances in the ability to diagnose genetic disorders have been made. The identification of disease-causing genes allows the development of gene-specific therapies with the ultimate goal to develop personalized medicines for each patient according to their own specific genetic defect. In-depth genotyping of many different genes has revealed that ~12% of inherited genetic disorders are caused by in-frame nonsense mutations. Nonsense (non-coding) mutations are caused by point mutations, which generate premature termination codons (PTCs) that cause premature translational termination of the mRNA, and subsequently inhibit normal full-length protein expression. Recently, a gene-based therapeutic approach for genetic diseases caused by nonsense mutations has emerged, namely the so-called translational read-through (TR) therapy. Read-through therapy is based on the discovery that small molecules, known as TR-inducing drugs (TRIDs), allow the translation machinery to suppress a nonsense codon, elongate the nascent peptide chain, and consequently result in the synthesis of full-length protein. Several TRIDs are currently under investigation and research has been performed on several genetic disorders caused by nonsense mutations over the years. These findings have raised hope for the usage of TR therapy as a gene-based pharmacogenetic therapy for nonsense mutations in various genes responsible for a variety of genetic diseases.

Autoren

Kerstin Nagel-Wolfrum
Fabian Möller
Inessa Penner
Timor Baasov
Uwe Wolfrum

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/26886021

DOI

10.1007/s40259-016-0157-6

eISSN

1179-190X

Ausgabe der Veröffentlichung

2

Zeitschrift

BioDrugs

Schlüsselwörter

Animals
Codon, Nonsense
Genetic Diseases, Inborn
Genetic Therapy
Genotype
Humans
Pharmaceutical Preparations
RNA, Messenger

Sprache

eng

Country

New Zealand

Paginierung

49 - 74

PII

10.1007/s40259-016-0157-6

Datum der Veröffentlichung

2016

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2016

Titel

Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs).

Sub types

Journal Article
Research Support, Non-U.S. Gov't
Review

Ausgabe der Zeitschrift

30

Data source: PubMed

Targeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs)

Tools