A high-content drug screening strategy to identify protein level modulators for genetic diseases: A proof-of-principle in autosomal dominant leukodystrophy.
ADLD
LMNB1
alvespimycin
dosage-sensitive gene
lamin B1
pharmacological screening
rare disease
therapy
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
21
05
2020
revised:
09
10
2020
accepted:
24
11
2020
pubmed:
1
12
2020
medline:
1
4
2022
entrez:
30
11
2020
Statut:
ppublish
Résumé
In genetic diseases, the most prevalent mechanism of pathogenicity is an altered expression of dosage-sensitive genes. Drugs that restore physiological levels of these genes should be effective in treating the associated conditions. We developed a screening strategy, based on a bicistronic dual-reporter vector, for identifying compounds that modulate protein levels, and used it in a pharmacological screening approach. To provide a proof-of-principle, we chose autosomal dominant leukodystrophy (ADLD), an ultra-rare adult-onset neurodegenerative disorder caused by lamin B1 (LMNB1) overexpression. We used a stable Chinese hamster ovary (CHO) cell line that simultaneously expresses an AcGFP reporter fused to LMNB1 and a Ds-Red normalizer. Using high-content imaging analysis, we screened a library of 717 biologically active compounds and approved drugs, and identified alvespimycin, an HSP90 inhibitor, as a positive hit. We confirmed that alvespimycin can reduce LMNB1 levels by 30%-80% in five different cell lines (fibroblasts, NIH3T3, CHO, COS-7, and rat primary glial cells). In ADLD fibroblasts, alvespimycin reduced cytoplasmic LMNB1 by about 50%. We propose this approach for effectively identifying potential drugs for treating genetic diseases associated with deletions/duplications and paving the way toward Phase II clinical trials.
Substances chimiques
Lamin Type B
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
102-116Informations de copyright
© 2020 Wiley Periodicals LLC.
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