Tiny capsule that delivers CRISPR gene therapy to the brain could be used to target glioblastoma tumours
20 April 2022
A nanocapsule that delivers the gene-editing tool CRISPR to the brain could be used to treat one of the most aggressive forms of brain cancer, called glioblastoma. In tests in mouse models of the condition, the technique halted tumour growth and extended lifespan.
CRISPR is a tool for adding, removing or altering genetic material inside cells, and has great promise for treating some conditions. It is accurate and cheap compared to other gene-editing methods, but it is currently difficult to use in the brain.
Most methods for targeting the brain involve either direct injection into brain tissue or inserting CRISPR into non-disease-causing viruses and then injecting these into the bloodstream. These methods have significant drawbacks, including potential injury to brain tissue or, in the case of viruses, difficulty in pinpointing delivery, meaning there is an increased risk of serious side effects such as unintended genetic mutations.
By packaging CRISPR in specially designed nanocapsules – tiny non-toxic polymer bubbles – researchers have been able to address these problems elsewhere in the body, but there have been challenges using this technique in the brain. That is largely because it is hard to get past the blood brain barrier: blood vessels in the brain are less porous than elsewhere in the body, something that usually helps to protect against harmful invaders.
“Brain diseases, including brain tumours, are particularly challenging to target therapeutically because of the blood brain barrier,” says neurosurgeon Dimitris Placantonakis at the New York University Grossman School of Medicine.
Now, Yan Zou at the Henan-Macquarie University Joint Center for Biomedical Innovation in China and colleagues have designed a new kind of nanocapsule that was able to cross this barrier and deliver CRISPR therapy in mice with brain tumours.
In this instance, the researchers used CRISPR to target a gene called PLK1, which regulates the development of new cells, and in glioblastoma essentially acts in overdrive. In the study, tumour growth stalled in mice treated with a single tail injection and they had a median survival time of 68 days, compared with 24 days or less in control groups, which were given microcapsules containing either non-targeted genetic material or saline solution. What’s more, the new technique caused negligible – fewer than 0.5 per cent – unwanted genetic mutations in tissue where they are more likely to arise.
At just about 30 nanometres in size, the nanocapsule is much smaller than many currently in use, which often range from 100 to 500 nanometres. It also has a nearly neutral charge. Positively charged nanoparticles are toxic to the body, so usually get targeted and destroyed in the bloodstream.
“To the best of our knowledge, our nanocapsules represent a foremost noninvasive and nonviral strategy for effective and safe brain delivery and [glioblastoma] gene therapy,” Zou and colleagues wrote in a paper published this week in Science Advances.
“This is really exciting,” says Placantonakis. Much more testing is needed, he says, but it is a very encouraging first step. The researchers are hopeful that this technique could also be useful for treating brain conditions beyond glioblastoma.
Journal reference: Science Advances, DOI: 10.1126/sciadv.abm8011
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