Evidence map›Paper›PMID 33184574›Full record

ArticleCellular and molecular bioengineering2020

Structure-Guided Molecular Engineering of a Vascular Endothelial Growth Factor Antagonist to Treat Retinal Diseases.

Rakeeb Kureshi, Angela Zhu, Jikui Shen, Stephany Y Tzeng, Leilani R Astrab, Paul R Sargunas, Jordan J Green, Peter A Campochiaro, Jamie B Spangler

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cellular and molecular bioengineering, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.2field-weighted citation impact, top 50% of its field
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

3 citing papers in PubMed, 4 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
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

9 authors at 1 institution in 1 country.

Rakeeb KureshiDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Angela ZhuDepartment of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD USA.
Jikui ShenDepartment of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Stephany Y TzengDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Leilani R AstrabDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Paul R SargunasDepartment of Chemical & Biomolecular Engineering, Johns Hopkins University, Baltimore, MD USA.
Jordan J GreenDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Peter A CampochiaroDepartment of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD USA.
Jamie B SpanglerDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD USA.ORCID 0000-0001-8187-3732
Johns Hopkins University · US

Funding

Suprachoroidal nonviral gene transfer of engineered VEGF antagonistsR01EY031097 · NEI · JOHNS HOPKINS UNIVERSITY · PI CAMPOCHIARO, PETER A, GREEN, JORDAN · 2020 to 2023
$2.4M
Gene Delivery Nanoparticles to Treat GlioblastomaR01CA228133 · NCI · JOHNS HOPKINS UNIVERSITY · PI GREEN, JORDAN · 2019 to 2023
$1.9M
NCI NIH HHS R01 CA228133NEI NIH HHS R01 EY031097
6 · The paper itself

Abstract

backgroundOcular neovascularization is a hallmark of retinal diseases including neovascular age-related macular degeneration and diabetic retinopathy, two leading causes of blindness in adults. Neovascularization is driven by the interaction of soluble vascular endothelial growth factor (VEGF) ligands with transmembrane VEGF receptors (VEGFR), and inhibition of the VEGF pathway has shown tremendous clinical promise. However, anti-VEGF therapies require invasive intravitreal injections at frequent intervals and high doses, and many patients show incomplete responses to current drugs due to the lack of sustained VEGF signaling suppression.

methodsWe synthesized insights from structural biology with molecular engineering technologies to engineer an anti-VEGF antagonist protein. Starting from the clinically approved decoy receptor protein aflibercept, we strategically designed a yeast-displayed mutagenic library of variants and isolated clones with superior VEGF affinity compared to the clinical drug. Our lead engineered protein was expressed in the choroidal space of rat eyes via nonviral gene delivery.

resultsUsing a structure-informed directed evolution approach, we identified multiple promising anti-VEGF antagonist proteins with improved target affinity. Improvements were primarily mediated through reduction in dissociation rate, and structurally significant convergent sequence mutations were identified. Nonviral gene transfer of our engineered antagonist protein demonstrated robust and durable expression in the choroid of treated rats one month post-injection.

conclusionsWe engineered a novel anti-VEGF protein as a new weapon against retinal diseases and demonstrated safe and noninvasive ocular delivery in rats. Furthermore, our structure-guided design approach presents a general strategy for discovery of targeted protein drugs for a vast array of applications.

Indexed as

Affinity engineeringDirected evolutionNonviral gene therapyOcular neovascularizationVascular endothelial growth factor receptor

Identifiers

PMID33184574
PMCPMC7596137
OpenAlexW3046413099

What OpenQuestion 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 OpenQuestion graph.