Unlocking the Potential of CRISPR/Cas13 for Antiviral Therapy

RNA viruses like SARS-CoV-2 demand new solutions. CRISPR/Cas13 tools work well against these viruses in the cell's nucleus, but not in the cytoplasm, where many replicate. Researchers at TUM and Helmholtz Munich have developed Cas13d-NCS, a new tool that effectively targets cytoplasmic RNA viruses. It achieves this by allowing nuclear CRISPR RNA molecules to reach the cytoplasm.

Proactive viral defense tactics and precision medicine are made possible by this development. The study was published in the Cell Discovery journal.

Breakthrough developments in antiviral therapy are becoming a vital tool in the battle against these infectious diseases as the world prepares for continued and future threats to global health from RNA viruses like the SARS-CoV-2 pandemic.

The investigation of CRISPR/Cas13 systems, which are well-known for their programmable RNA manipulation capabilities and have grown to be essential instruments for a variety of RNA targeting applications, is at the core of this innovation. Cas13d's effectiveness has been hindered, nevertheless, by its limitation to the nucleus of mammalian cells. This significantly reduced its usefulness in cytosolic applications, like antiviral therapies that can be programmed.

A Potent Antiviral Solution

This problem with Cas13d's cytosolic inactivity was successfully resolved by a scientific team led by Professor Wolfgang Wurst, Drs. Christoph Gruber and Florian Giesert (Institute of Developmental Genetics at Helmholtz Munich and Chair of Developmental Genetics at TUM), which worked closely with the teams of Dr. Gregor Ebert (Institute of Virology at Helmholtz Munich and TUM) and Prof. Andreas Pichlmair (Institute of Virology at TUM).

The scientists created Cas13d-NCS, a unique system that can transfer nuclear crRNAs into the cytosol, as a transformative solution after carefully screening and optimizing the system. Short RNA molecules known as crRNAs, or CRISPR RNAs, direct the CRISPR-Cas complex to particular target sequences for exact modifications.

With previously unheard-of precision, the protein/crRNA complex in the cytosol targets and degrades complementary RNAs. Unlocking the full potential of Cas13d as a programmable antiviral tool, Cas13d-NCS outperforms its predecessors with remarkable efficiency in degrading mRNA targets and neutralizing self-replicating RNA, including replicating sequences of the Venezuelan equine encephalitis (VEE) RNA virus and several variants of SARS-CoV-2.

Redefining the Landscape of RNA Virus Therapeutics

This noteworthy accomplishment is a critical step in the fight against pandemics and in fortifying defenses against similar outbreaks in the future. Because the study makes it possible to manipulate the subcellular localization of CRISPR-based interventions strategically, its significance extends beyond conventional antiviral strategies and CRISPR systems and ushers in a new era of precision medicine.

This breakthrough in antiviral development with Cas13d-NCS marks a pivotal moment in our ongoing battle against RNA viruses. This achievement showcases the power of collaborative innovation and human ingenuity in our quest for a healthier and more resilient world.”

Wolfgang Wurst, Professor and Study Coordinator, Helmholtz Munich

Source:
Journal reference:

Gruber, C., et al. (2024) Engineered, nucleocytoplasmic shuttling Cas13d enables highly efficient cytosolic RNA targeting. Cell Discovery. doi.org/10.1038/s41421-024-00672-1

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