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Immune Response Activated by RNA Splicing Opens Targeted Therapies
In a new study published in Nature Communications titled, “Native long-read RNA sequencing of human monocytes reveals activation-induced alternative splicing toward functional isoforms,” researchers at University Medical Center (UMC) Utrecht have uncovered a previously underappreciated mechanism that helps immune cells respond rapidly to infections. The team showed that alternative RNA splicing plays a central role in shaping immune responses. The results provide new insights into immune-mediated diseases, such as infections, rheumatoid arthritis and lupus, and open the door to more targeted therapies.
The study focused on monocytes, a type of innate immune cell that acts as a first responder to pathogens. Using long-read RNA sequencing, the authors generated a comprehensive map of full-length RNA transcripts in human monocytes before and after activation. They identified more than 24,000 isoforms, the majority of which have never been described, revealing a previously hidden layer of molecular complexity.
Notably, immune activation triggers widespread ‘isoform switching.’ Rather than simply turning genes on or off, monocytes shift toward producing longer, fully functional RNA variants that are more likely to be translated into proteins. These isoforms contain complete coding sequences, fewer non-coding interruptions, and greater structural complexity, all features associated with more effective protein production.
“In our study we also confirmed that these RNA changes have real functional consequences,” said Jorg van Loosdregt, PhD, associate professor at UMC Utrecht and corresponding author of the study. “By integrating data on protein synthesis and ribosome activity, we demonstrated that the observed isoform shifts are linked to increased production of immune effector proteins. This shows that alternative splicing directly enhances the cell’s ability to respond to infection or inflammation.”
While previous studies have linked conditions, such as rheumatoid arthritis and lupus, to genetic variation affecting RNA splicing, the study demonstrates that disease mechanisms may also depend on which isoforms are produced and how efficiently they are translated into proteins.
“Our study underscores the importance of studying gene regulation at the isoform level. Traditional methods may overlook critical changes that only become visible with full-length RNA analysis,” said van Loosdregt. “The adoption of long-read sequencing technologies could therefore transform research into immune function and disease mechanisms.”
Emerging approaches, such as antisense oligonucleotides or drugs that influence splicing factors, may enable more precise modulation of the immune system and the development of targeted treatments for immune-mediated diseases.
The post Immune Response Activated by RNA Splicing Opens Targeted 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).
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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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