Publications by authors named "Holly Digby"
The 3' untranslated region (3'UTR) plays a crucial role in determining mRNA stability, localisation, translation and degradation. Cap analysis of gene expression (CAGE), a method for the detection of capped 5' ends of mRNAs, additionally reveals a large number of apparently 5' capped RNAs derived from locations within the body of the transcript, including 3'UTRs. Here, we provide direct evidence that these 3'UTR-derived RNAs are indeed capped and widespread in mammalian cells.
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- The study focuses on TDP-REG, a tool designed to take advantage of the specific splicing changes caused by TDP-43 loss of function (TDP-LOF), which is linked to ALS and similar neurodegenerative diseases.
- It utilizes a deep learning algorithm, SpliceNouveau, to create customizable splicing events that enhance protein expression correlated with the disease state, both in lab settings (in vitro) and in living organisms (in vivo).
- TDP-REG allows for targeted editing of genetic sequences, potentially correcting harmful splicing effects and leading to new precision treatment approaches for disorders related to TDP-43.
A system enabling the expression of therapeutic proteins specifically in diseased cells would be transformative, providing greatly increased safety and the possibility of pre-emptive treatment. Here we describe "TDP-REG", a precision medicine approach primarily for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which exploits the cryptic splicing events that occur in cells with TDP-43 loss-of-function (TDP-LOF) in order to drive expression specifically in diseased cells. In addition to modifying existing cryptic exons for this purpose, we develop a deep-learning-powered algorithm for generating customisable cryptic splicing events, which can be embedded within virtually any coding sequence.
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