Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations

Abstract

AbstractThe eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30–50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.

Autoren

KERSTIN NAGEL-WOLFRUM
FABIAN MÖLLER
INESSA PENNER
UWE WOLFRUM

DOI

10.1017/s0952523814000194

eISSN

1469-8714

ISSN

0952-5238

Ausgabe der Veröffentlichung

4-5

Zeitschrift

Visual Neuroscience

Sprache

en

Online publication date

2014

Paginierung

309 - 316

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Cambridge University Press (CUP)

Herausgeber URL

http://dx.doi.org/10.1017/s0952523814000194

Datum der Datenerfassung

2023

Titel

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations

Ausgabe der Zeitschrift

31

Datenquelle: Crossref

Abstract

The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.

Addresses

Department of Cell and Matrix Biology,Institute of Zoology,Johannes Gutenberg-University of Mainz,Mainz,Germany.

Autoren

Kerstin Nagel-Wolfrum
Fabian Möller
Inessa Penner
Uwe Wolfrum

DOI

10.1017/s0952523814000194

eISSN

1469-8714

Externe Identifier

PubMed Identifier: 24912600

Open access

false

ISSN

0952-5238

Ausgabe der Veröffentlichung

4-5

Zeitschrift

Visual neuroscience

Schlüsselwörter

Animals
Humans
Oxadiazoles
Aminoglycosides
Codon, Nonsense
Signal Transduction
Protein Biosynthesis
Retinal Dystrophies
Genetic Therapy

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

309 - 316

Datum der Veröffentlichung

2014

Status

Published

Datum der Datenerfassung

2014

Titel

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations.

Sub types

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

Ausgabe der Zeitschrift

31

Datenquelle: Europe PubMed Central

Abstract

The eye has become an excellent target for gene therapy, and gene augmentation therapy of inherited retinal disorders has made major progress in recent years. Nevertheless, a recent study indicated that gene augmentation intervention might not stop the progression of retinal degeneration in patients. In addition, for many genes, viral-mediated gene augmentation is currently not feasible due to gene size and limited packaging capacity of viral vectors as well as expression of various heterogeneous isoforms of the target gene. Thus, alternative gene-based strategies to stop or delay the retinal degeneration are necessary. This review focuses on an alternative pharmacologic treatment strategy based on the usage of translational read-through inducing drugs (TRIDs) such as PTC124, aminoglycoside antibiotics, and designer aminoglycosides for overreading in-frame nonsense mutations. This strategy has emerged as an option for up to 30-50% of all cases of recessive hereditary retinal dystrophies. In-frame nonsense mutations are single-nucleotide alterations within the gene coding sequence resulting in a premature stop codon. Consequently, translation of such mutated genes leads to the synthesis of truncated proteins, which are unable to fulfill their physiologic functions. In this context, application of TRIDs facilitates the recoding of the premature termination codon into a sense codon, thus restoring syntheses of full-length proteins. So far, clinical trials for non-ocular diseases have been initiated for diverse TRIDs. Although the clinical outcome is not analyzed in detail, an excellent safety profile, namely for PTC124, was clearly demonstrated. Moreover, recent data demonstrated sustained read-through efficacies of nonsense mutations causing retinal degeneration, as manifested in the human Usher syndrome. In addition, a strong retinal biocompatibility for PTC124 and designer aminoglycosides has been demonstrated. In conclusion, recent progress emphasizes the potential of TRIDs as an alternative pharmacologic treatment strategy for treating nonsense mutation-based retinal disorders.

Autoren

Kerstin Nagel-Wolfrum
Fabian Möller
Inessa Penner
Uwe Wolfrum

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/24912600

DOI

10.1017/S0952523814000194

eISSN

1469-8714

Ausgabe der Veröffentlichung

4-5

Zeitschrift

Vis Neurosci

Schlüsselwörter

Aminoglycosides
Animals
Codon, Nonsense
Genetic Therapy
Humans
Oxadiazoles
Protein Biosynthesis
Retinal Dystrophies
Signal Transduction

Sprache

eng

Country

England

Paginierung

309 - 316

PII

S0952523814000194

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2015

Titel

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations.

Sub types

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

Ausgabe der Zeitschrift

31

Datenquelle: PubMed

Translational read-through as an alternative approach for ocular gene therapy of retinal dystrophies caused by in-frame nonsense mutations

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