scholarly journals Towards Clinical Trials in Fuchs Endothelial Corneal Dystrophy: Classification and Outcome Measures—The Bowman Club Lecture 2019

2019 ◽  
Vol 4 (1) ◽  
pp. e000321 ◽  
Author(s):  
Sanjay V Patel
Keyword(s):  
Clinical Trials ◽  
Outcome Measures ◽  
Trinucleotide Repeat ◽  
Clinical Investigation ◽  
Corneal Dystrophy ◽  
Underlying Disease ◽  
Surgical Removal ◽  
Disease Mechanisms ◽  
Transcription Factor 4 ◽  
Careful Thought

The surgical treatment of Fuchs endothelial corneal dystrophy (FECD) has advanced dramatically over the last two decades. Penetrating keratoplasty has been superseded by various iterations of endothelial keratoplasty, and currently, surgical removal of host Descemet membrane without keratoplasty is being investigated. These surgical advances have been accompanied by significant improvement of our understanding of the underlying disease mechanisms, not least the discovery that FECD in western populations is predominantly an intronic trinucleotide repeat expansion disorder in the transcription factor 4 gene that results in RNA toxicity and mis-splicing. Understanding the disease mechanisms augurs well for developing targeted molecular medical therapies, which will require careful clinical investigation through trials to prove their efficacy and safety. As the field advances towards clinical trials, investigators should carefully define the disease state being treated and consider the options for outcome measures relevant to the type of intervention. FECD, and the outcomes of interventions to treat the disease, can be measured in terms of corneal morphology, corneal function and clinical impact. Standardising the approach for defining FECD and careful thought about the outcomes of intervention that are reported will help make the results of future trials for FECD applicable in clinical practice.

scholarly journals Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene in Thai patients with Fuchs endothelial corneal dystrophy

Eye ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 880-885 ◽  
Author(s):  
Naoki Okumura ◽  
Vilavun Puangsricharern ◽  
Raina Jindasak ◽  
Noriko Koizumi ◽  
Yuya Komori ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Repeat Expansion ◽  
Trinucleotide Repeat Expansion ◽  
Transcription Factor 4

scholarly journals The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Alex Sirp ◽  
Kristian Leite ◽  
Jürgen Tuvikene ◽  
Kaja Nurm ◽  
Mari Sepp ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Protein Isoforms ◽  
Compensatory Mechanism ◽  
Alternative Promoters ◽  
Rna Seq ◽  
Increased Risk ◽  
Specific Manner ◽  
Transcription Factor 4

Abstract The CTG trinucleotide repeat (TNR) expansion in Transcription factor 4 (TCF4) intron 3 is the main cause of Fuchs’ endothelial corneal dystrophy (FECD) and may confer an increased risk of developing bipolar disorder (BD). Usage of alternative 5′ exons for transcribing the human TCF4 gene results in numerous TCF4 transcripts which encode for at least 18 N-terminally different protein isoforms that vary in their function and transactivation capability. Here we studied the TCF4 region containing the CTG TNR and characterized the transcription initiation sites of the nearby downstream 5′ exons 4a, 4b and 4c. We demonstrate that these exons are linked to alternative promoters and show that the CTG TNR expansion decreases the activity of the nearby downstream TCF4 promoters in primary cultured neurons. We confirm this finding using two RNA sequencing (RNA-seq) datasets of corneal endothelium from FECD patients with expanded CTG TNR in the TCF4 gene. Furthermore, we report an increase in the expression of various other TCF4 transcripts in FECD, possibly indicating a compensatory mechanism. We conclude that the CTG TNR affects TCF4 expression in a transcript-specific manner both in neurons and in the cornea.

scholarly journals A Common Trinucleotide Repeat Expansion within the Transcription Factor 4 (TCF4, E2-2) Gene Predicts Fuchs Corneal Dystrophy

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49083 ◽  
Author(s):  
Eric D. Wieben ◽  
Ross A. Aleff ◽  
Nirubol Tosakulwong ◽  
Malinda L. Butz ◽  
W. Edward Highsmith ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Repeat Expansion ◽  
Trinucleotide Repeat Expansion ◽  
Transcription Factor 4

scholarly journals Lower Fractions of TCF4 Transcripts Spanning over the CTG18.1 Trinucleotide Repeat in Human Corneal Endothelium

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2006
Author(s):  
Ida Maria Westin ◽  
Andreas Viberg ◽  
Berit Byström ◽  
Irina Golovleva
Keyword(s):  
Endothelial Cells ◽  
Corneal Endothelium ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Corneal Dystrophy ◽  
Digital Pcr ◽  
Corneal Endothelial Cells ◽  
Transcription Start Sites ◽  
Gradual Loss ◽  
Transcription Factor 4

Fuchs’ endothelial corneal dystrophy (FECD) is a bilateral disease of the cornea caused by gradual loss of corneal endothelial cells. Late-onset FECD is strongly associated with the CTG18.1 trinucleotide repeat expansion in the Transcription Factor 4 gene (TCF4), which forms RNA nuclear foci in corneal endothelial cells. To date, 46 RefSeq transcripts of TCF4 are annotated by the National Center of Biotechnology information (NCBI), however the effect of the CTG18.1 expansion on expression of alternative TCF4 transcripts is not completely understood. To investigate this, we used droplet digital PCR for quantification of TCF4 transcripts spanning over the CTG18.1 and transcripts with transcription start sites immediately downstream of the CTG18.1. TCF4 expression was analysed in corneal endothelium and in whole blood of FECD patients with and without CTG18.1 expansion, in non-FECD controls without CTG18.1 expansion, and in five additional control tissues. Subtle changes in transcription levels in groups of TCF4 transcripts were detected. In corneal endothelium, we found a lower fraction of transcripts spanning over the CTG18.1 tract compared to all other tissues investigated.

Digital Technology in Clinical Trials for Multiple Sclerosis: a systematic review. (Preprint)

2020 ◽  
Author(s):  
Marcello De Angelis ◽  
Luigi Lavorgna ◽  
Antonio Carotenuto ◽  
Martina Petruzzo ◽  
Roberta Lanzillo ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Outcome Measures ◽  
Digital Technology ◽  
Clinical Trial Design ◽  
Motor Rehabilitation ◽  
Robot Assisted ◽  
Future Directions ◽  
Treatment Side Effects

BACKGROUND Clinical trials in multiple sclerosis (MS) have leveraged the use of digital technology to overcome limitations in treatment and disease monitoring. OBJECTIVE To review the use of digital technology in concluded and ongoing MS clinical trials. METHODS In March 2020, we searched for “multiple sclerosis” and “trial” on pubmed.gov and clinicaltrials.gov using “app”, “digital”, “electronic”, “internet” and “mobile” as additional search words, separately. Overall, we included thirty-five studies. RESULTS Digital technology is part of clinical trial interventions to deliver psychotherapy and motor rehabilitation, with exergames, e-training, and robot-assisted exercises. Also, digital technology has become increasingly used to standardise previously existing outcome measures, with automatic acquisitions, reduced inconsistencies, and improved detection of symptoms. Some trials have been developing new patient-centred outcome measures for the detection of symptoms and of treatment side effects and adherence. CONCLUSIONS We will discuss how digital technology has been changing MS clinical trial design, and possible future directions for MS and neurology research.

scholarly journals Use of connected digital products in clinical research following the COVID-19 pandemic: a comprehensive analysis of clinical trials

BMJ Open ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. e047341
Author(s):  
Caroline Marra ◽  
William J Gordon ◽  
Ariel Dora Stern
Keyword(s):  
Clinical Trials ◽  
Clinical Research ◽  
Outcome Measures ◽  
Remote Monitoring ◽  
Search Algorithm ◽  
Primary Outcome Measure ◽  
Secondary Outcome ◽  
Digital Products ◽  
Clinical Trial Registry ◽  
Before And After

ObjectivesIn an effort to mitigate COVID-19 related challenges for clinical research, the US Food and Drug Administration (FDA) issued new guidance for the conduct of ‘virtual’ clinical trials in late March 2020. This study documents trends in the use of connected digital products (CDPs), tools that enable remote patient monitoring and telehealth consultation, in clinical trials both before and after the onset of the pandemic.DesignWe applied a comprehensive text search algorithm to clinical trial registry data to identify trials that use CDPs for remote monitoring or telehealth. We compared CDP use in the months before and after the issuance of FDA guidance facilitating virtual clinical trials.SettingAll trials registered on ClinicalTrials.gov with start dates from May 2019 through February 2021.Outcome measuresThe primary outcome measure was the overall percentage of CDP use in clinical trials started in the 10 months prior to the pandemic onset (May 2019–February 2020) compared with the 10 months following (May 2020–February 2021). Secondary outcome measures included CDP usage by trial type (interventional, observational), funder type (industry, non-industry) and diagnoses (COVID-19 or non-COVID-19 participants).ResultsCDP usage in clinical trials increased by only 1.65 percentage points, from 14.19% (n=23 473) of all trials initiated in the 10 months prior to the pandemic onset to 15.84% (n=26 009) of those started in the 10 months following (p<0.01). The increase occurred primarily in observational studies and non-industry funded trials and was driven entirely by CDP usage in trials for COVID-19.ConclusionsThese findings suggest that in the short-term, new options created by regulatory guidance to stimulate telehealth and remote monitoring were not widely incorporated into clinical research. In the months immediately following the pandemic onset, CDP adoption increased primarily in observational and non-industry funded studies where virtual protocols are likely medically necessary due to the participants’ COVID-19 diagnosis.

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