Scientists profile FDA-approved drugs to potentially treat hundreds of
genetic disorders
Date:
February 3, 2022
Source:
University of California - Riverside
Summary:
Nonsense-mediated RNA decay, or NMD, is an evolutionarily conserved
molecular mechanism in which potentially defective messenger RNAs,
or mRNAs, are degraded. Its disruption can lead to neurological
disorders, immune diseases, cancers, and other pathologies. A
team of biomedical scientists has designed a simple and robust
method to determine the effects of drugs on NMD. The researchers
profiled all current Food and Drug Administration-approved drugs
to identify NMD modulators, which could potentially help treat
hundreds of disorders associated with NMD.
FULL STORY ========================================================================== Nonsense-mediated RNA decay, or NMD, is an evolutionarily conserved
molecular mechanism in which potentially defective messenger RNAs, or
mRNAs, are degraded. By reducing errors in gene expression, it serves
as an RNA quality control and gene regulatory mechanism. Its disruption
can lead to neurological disorders, immune diseases, cancers, and other pathologies.
==========================================================================
A team of biomedical scientists at the University of California,
Riverside, has designed a simple and robust method to determine the
effects of drugs on NMD.
The researchers profiled all current Food and Drug Administration-approved drugs to identify NMD modulators, which could potentially help treat
hundreds of disorders associated with NMD.
"These drugs, by modulating cellular NMD efficiency, can potentially
alleviate symptoms of genetic disorders caused by nonsense mutations,"
said Sika Zheng, an associate professor of biomedical sciences in
the School of Medicine, who led the study that appears in the journal
Molecular Therapy -- Nucleic Acids.
"Two examples are Duchenne muscular dystrophy and cystic fibrosis."
Cells have surveillance mechanisms to target defective mRNAs. Without
these mechanisms, which operate in the cell nucleus and cytoplasm, errors
in the synthesis of proteins could result. NMD is one of the best-studied
RNA surveillance pathways. The term "nonsense" in its name refers to a
type of mutation. NMD plays an important role in cell cycle regulation,
cell viability, and DNA damage response. It also serves as a barrier to
virus infection.
"NMD degrades aberrant mRNAs and prevents their expression," Zheng
said. "More than 20% of monogenic diseases -- which means hundreds of
rare diseases, including sickle cell anemia -- are attributed to genetic mutations directly targeted by NMD. Excessive aberrant mRNAs also play
a role in Lou Gehrig's disease and myelodysplastic syndromes. Therefore,
NMD modulation can help modify diseases outcomes. Several NMD modulators
we identified can be tested in animal models of aforementioned diseases."
Zheng explained that current FDA-approved drugs are not known to
target NMD.
They have not been examined closely for their effect on cellular NMD
activity.
For this study, Zheng and his team first developed a robust sensitive
assay or test, termed AS-NMD assay, that quantitatively measures cellular
NMD activity.
They then obtained a library of 704 FDA-approved drugs. They treated
cells with each of these drugs and measured the cellular responses using
the AS-NMD assay.
"We wanted to know whether the FDA-approved drugs can be repurposed to
modulate NMD," he said. "So we treated cells with each FDA-approved
drug and tested whether cellular NMD activity was affected. We found
one drug had a strong effect on NMD; four drugs had mild effects. We
now have solid information for the effect of 704 FDA-approved drugs on
NMD. What made this possible is the method we developed, without which profiling 704 drugs to such a precision level would be unthinkable. Old
methods are either too tedious or not precise enough.
Zheng believes the NMD-modulatory drugs should be further investigated for their molecular targets and be optimized and repurposed for NMD-associated diseases.
"Nonsense mutation-associated disorders are orphan diseases with a wide
range of varied symptoms," he said. "We should think of targeting their commonality: the associated NMD pathway." Next, the research team plans
to do animal testing of some drug candidates.
They also plan to scale up their assay to profile larger chemical
libraries.
The research was funded by the National Institutes of Health and the
UCR Center for Molecular and Translational Medicine.
========================================================================== Story Source: Materials provided by
University_of_California_-_Riverside. Original written by Iqbal
Pittalwala. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Jingrong Zhao, Zhelin Li, Ruchira Puri, Kelvin Liu, Israel Nunez,
Liang
Chen, Sika Zheng. Molecular profiling of individual FDA-approved
clinical drugs identifies modulators of nonsense-mediated mRNA
decay. Molecular Therapy - Nucleic Acids, 2022; 27: 304 DOI:
10.1016/j.omtn.2021.12.003 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220203161240.htm
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