Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F18%3A10376571" target="_blank" >RIV/00216208:11110/18:10376571 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064165:_____/18:10376571

Výsledek na webu

<a href="https://doi.org/10.1016/j.ajhg.2018.02.010" target="_blank" >https://doi.org/10.1016/j.ajhg.2018.02.010</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ajhg.2018.02.010" target="_blank" >10.1016/j.ajhg.2018.02.010</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity

Popis výsledku v původním jazyce

Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (&gt;= 50 copies) of a non-coding trinucleotide repeat in TCF4 confers &gt;76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.

Název v anglickém jazyce

Antisense Therapy for a Common Corneal Dystrophy Ameliorates TCF4 Repeat Expansion-Mediated Toxicity

Popis výsledku anglicky

Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (&gt;= 50 copies) of a non-coding trinucleotide repeat in TCF4 confers &gt;76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10600 - Biological sciences

Projekt

<a href="/cs/project/GA17-12355S" target="_blank" >GA17-12355S: Mechanismy vzniku primárních onemocnění endotelu rohovky</a><br>

Návaznosti

S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

The American Journal of Human Genetics

ISSN

0002-9297

e-ISSN

—

Svazek periodika

102

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

528-539

Kód UT WoS článku

000429340800002

EID výsledku v databázi Scopus

2-s2.0-85042642502