Evidence map›Paper›PMID 42556338›Full record

ArticleCell chemical biology2026

An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies.

Roza Ogurlu, Eliya B Sanchez, Joshua A Hull, Sophia M Fergione, Vivian Yudistyra, Gabriela M Webb, Helen L Wu, Cleiton T Pessoa, Matthew C Humkey, Sofia K Potter and 4 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Roza OgurluDepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Eliya B SanchezDepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Joshua A HullDepartment of Surgery, Duke University School of Medicine, Durham, NC 27708, USA.
Sophia M FergioneDepartment of Surgery, Duke University School of Medicine, Durham, NC 27708, USA.
Vivian YudistyraDepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Gabriela M WebbOregon National Primate Research Center and Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97239, USA.
Helen L WuOregon National Primate Research Center and Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97239, USA.
Cleiton T PessoaOregon National Primate Research Center and Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97239, USA.
Matthew C HumkeyOregon National Primate Research Center and Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97239, USA.
Sofia K PotterOregon National Primate Research Center and Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97239, USA.
Alan RosalesDepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Heather A VincentDepartment of Surgery, Duke University School of Medicine, Durham, NC 27708, USA.
Jonah B SachaOregon National Primate Research Center and Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97239, USA.
Aravind AsokanDepartment of Biomedical Engineering, Duke University, Durham, NC 27708, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27708, USA; Department of Molecular Genetics & Microbiology, Duke University School of Medicine, Durham, NC 27708, USA. Electronic address: aravind.asokan@duke.edu.

Funding

Determinants of AAV TropismR01HL089221 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Aravind Asokan · 2009 to 2026
$8.1M
ChimeraX -- Next Generation Visualization and Analysis Software for Multiscale ModelingR01GM129325 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI FERRIN, THOMAS E · 2018 to 2025
$5.2M
Evolving Novel AAV Vectors for Gene Therapy to Cure HIVR01AI166969 · NIAID · OREGON HEALTH & SCIENCE UNIVERSITY · PI ASOKAN, ARAVIND, SACHA, JONAH B. · 2022 to 2025
$4.9M
Dissecting AAV silencing in humanized miceR01DK134408 · NIDDK · DUKE UNIVERSITY · PI Aravind Asokan, Karl-Dimiter Bissig · 2023 to 2026
$2.4M
NHLBI NIH HHS R01 HL089221NIAID NIH HHS R01 AI166969NIDDK NIH HHS R01 DK134408NIGMS NIH HHS R01 GM129325
6 · The paper itself

Abstract

Therapeutic protein overexpression can overwhelm endoplasmic reticulum (ER) folding capacity, trigger unfolded protein response (UPR) signaling, and compromise the safety of gene and mRNA therapies. Here, we engineer stress-responsive RNA rheostats that couple transgene expression to endogenous ER stress sensing. Short RNA elements derived from X-box-binding protein 1 (XBP1) mRNA undergo inositol-requiring enzyme 1α (IRE1α)-dependent splicing under ER stress, inducing a frameshift that attenuates downstream protein expression. XBP1 switches function across DNA and mRNA delivery platforms and regulate the expression of fluorescent reporters, coagulation factor VIII, and Leronlimab, a therapeutic anti-CCR5 monoclonal antibody. Switch activation reduces ER stress markers while preserving expression under homeostatic conditions. We further demonstrate the regulation of Leronlimab expression in vivo using recombinant adeno-associated virus vectors. Together, these findings establish programmable RNA feedback control as a strategy for linking cellular proteostasis to therapeutic protein expression and improving the safety of gene and mRNA therapies.

Indexed as

Endoplasmic Reticulum StressGenetic TherapyRNA, MessengerAnimalsEndoribonucleasesGene Therapy AgentsHumansMiceProtein Serine-Threonine KinasesRNA SplicingUnfolded Protein ResponseX-Box Binding Protein 1EndoribonucleasesProtein Serine-Threonine KinasesRNA, MessengerX-Box Binding Protein 1endoplasmic reticulum stressER stressgene therapymRNA therapyprotein overexpressionrheostatRNA splicingRNA switchesunfolded protein response

Identifiers

PMID42556338
PMCPMC13501694

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.