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Age-Related Inflammation Linked to R-Loop Nucleic Acids, Opens Therapies
In a new study published in Nature Aging titled, “Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging,” researchers from the University of Texas (UT) MD Anderson Cancer Center have uncovered a previously unknown connection between R-loop nucleic acid structures and age-related inflammation or inflammaging. The results support new intervention options for chronic inflammation and subsequent health conditions.
In preclinical models, the administration of KPT-330 (selinexor) prevented export of R-loops and led to significant improvement in inflammation, liver damage, fat gain, muscle loss and overall lifespan.
“Chronic, widespread inflammation is a driving factor in many age-related diseases, including cancer, and our research has discovered one reason why this happens,” said Rugang Zhang, PhD, professor and chair of Experimental Therapeutics at UT MD Anderson and corresponding author on the study. “Understanding the cause is the first step toward developing treatments. We saw encouraging results using a drug that has already been tested in humans, paving the way for potential clinical use to alleviate age-related conditions.”
Cells begin releasing signals that contribute to chronic inflammation once they enter senescence and stop dividing. Researchers have now pinpointed R-loops as a key component to modulating these inflammatory signals.
An R-loop is a temporary cellular structure created during transcription, when a double strand of RNA and DNA becomes tangled with a third displaced single strand of DNA. While R-loops are traditionally confined to the cell nucleus, the study found that cells in senescence increasingly export R-loops into the cytoplasm. These R-loops attach to fragments of DNA debris to trigger chronic inflammation.
This study identified the two proteins involved in exporting R-loops, DDX1 and XPO1. DDX1 attaches to the R-loop inside the nucleus to facilitate export. XPO1 allows the R-loops to be transported into the cytoplasm by forming a complex with DDX1.
Researchers administered KPT-330, a FDA-approved drug for treating multiple myeloma that blocks nuclear export. The R-loops remain trapped inside the nucleus and could not trigger an inflammatory response.
The study showed that shutting down nuclear export by blocking XPO1 in preclinical mouse models suppressed inflammaging, reduced liver fibrosis, lowered systemic inflammatory markers, and reversed age-related body composition changes.
In a separate experiment, the same inflammatory alarm enabled the immune system to find and eliminate precancerous cells. The authors state that future studies could explore blocking DDX1 specifically, instead of shutting down all nuclear export, to mitigate side effects.
The post Age-Related Inflammation Linked to R-Loop Nucleic Acids, Opens Therapies appeared first on GEN – Genetic Engineering and Biotechnology News.
Hosted by Drug Discovery World and supported by Sartorius and BioIVT, this webinar will explore the opportunities and challenges that exist within cancer research drug discovery and development.
You will hear from Dr Sudha Rao, Chief Scientific Officer of Kazia Therapeutics, Karol Budzik, PhD, Business Development Associate at Vyriad Therapeutics and Lars van der Veen, Chief Scientific Officer at iOnctura.
Presentations will cover how cancer treatments have shifted towards reprogramming the biology driving tumour growth, immune escape and treatment resistance, the trajectory that in vivo CAR-T treatments are taking, and how challenging tumours burdened by stroma and immune-mediated resistance can be tackled.
Q&A with the speakers follows the presentations.
The post New webinar: Tackling drug discovery challenges in cancer research appeared first on Drug Discovery World (DDW).
Amid the rise of psychedelics in the mental health space, researchers have begun to explore psilocybin as a treatment for chemotherapy-induced peripheral neuropathy.
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New Spectrometry Technique Could Aid Formulation Development
New Spectrometry Technique Could Aid Formulation Development
A new technique combining two forms of spectrometry could help biopharmaceutical companies improve their choice of formulation buffer for antibody manufacturing by revealing how molecular forms and three-dimensional shapes of complex biologics respond to their environment. That’s the view of Christian Bleiholder, PhD, a professor at Florida State University who helped develop the technique.
According to Bleiholder, what happens structurally when a complex biological molecule, such as an antibody or viral spike protein, binds to its target is currently poorly understood.
“This is where [this approach] can help with the bioprocessing and formulation,” he says, as structural changes “can affect the lifespan [of the product] and lead to issues, such as aggregation.”
Because antibodies are complex, existing techniques tend to be powerful at different levels of complexity, he explains. Mass spectrometry is particularly powerful for distinguishing molecular composition, while structural approaches such as X-ray crystallography and cryo-electron microscopy can provide high-resolution structural information.
The challenge is understanding the link between these things within a heterogeneous sample, he says.
To overcome this, Bleiholder and his team worked with Bruker Daltonics to develop Tandem-Trapped Ion Mobility Spectrometry (Tandem-TIMS). This combines tandem ion mobility spectrometry with tandem mass spectrometry to disentangle three overlapping layers of molecular complexity: molecular form, three-dimensional shape, and binding or assembly state, he says.
He explains that, if the proteins have different structures, they can be characterized with tandem ion mobility spectrometry, and then mass spectrometry can be used to look at their molecular forms and binding states.
Going forward, Bleiholder hopes the technique can be used for formulation development but also earlier, during drug discovery of new products, such as multi-specific antibodies, to determine which molecular states are important and how those change when a biologic engages its target. He also plans to look at automating the technique.
Bleiholder spoke about using Tandem-TIMS at the Bioprocessing Summit in Boston earlier this year.
The post New Spectrometry Technique Could Aid Formulation Development appeared first on GEN – Genetic Engineering and Biotechnology News.
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