Bacterial Syringe Ferries Protein Could Deliver Gene Therapy to Human Cells
The bacterium Photorhabdus asymbiotica uses molecular spikes to pierce a hole in the membranes of host cells – potentially developing a better drug-delivery system.
Some viruses and bacteria use a molecular ‘syringe’ to infect their hosts, which researchers have modified to potentially deliver therapeutic proteins into laboratory-grown human cells. This technique could offer a new way to administer protein-based drugs which, with further optimization, might be useful for delivering the components needed for CRISPR-Cas9 genome editing. Limited options have restricted most clinical trials to editing genomes because those cells can be reached using the current delivery methods
“It’s astonishing!” exclaimed Feng Jiang, a microbiologist at the Chinese Academy of Medical Sciences Institute of Pathogen Biology in Beijing. “It is a huge breakthrough.”
The technique was published in Nature on 29 March but will need more testing before it can be used in clinical trials in humans.
“One of the major bottlenecks for gene editing is delivery,” explained study co-author Feng Zhang, a molecular biologist at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, and an early pioneer of the CRISPR–Cas9 technique. “The reason we don’t see brain or kidney diseases getting tackled is because we don’t have good delivery systems.”
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Last year, Jiang and his colleagues reported that they could manipulate the syringe-like systems in the bioluminescent bacterium, Photorhabdus asymbiotica and load proteins from mammals, plants and fungi into the syringe.
“The bacterium can be viewed as a hired gun to kill this insect,” added co-author Joseph Kreitz, a molecular biologist at the Massachusetts Institute of Technology in Cambridge.
The bacterium lives inside nematodes and uses its syringe to transport a toxin into the cells of insects infected by the nematode. The toxin kills the insect and the nematode digests the remains.
In Zhang’s lab, Kreitz and his collaborators were working on ways to engineer the P. asymbiotica molecular syringe so that it would recognize human cells. They then loaded the syringes with various proteins, including Cas9 and toxins that could be used to kill cancer cells, and delivered them into human cells grown in the lab, and into the brains of mice.
Kreitz commented on the system’s inability, as of now, to transport the mRNA guide needed for CRISPR–Cas9 genome editing – but highlighted the technique’s flexibility to carry a larger capacity than the syringe’s usual load.
Sources: Kreitz, J, Friedrich, MJ, Guru, A et al. Programmable Protein Delivery with a Bacterial Contractile Injection System. Nature (2023); Nature Press Release
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