gene therapy is here, but our bodies are putting up a fight

Gene therapy has been a dream for decades. We could change the genes of a human embryo and implant it through IVF to prevent a child from developing certain hereditary disorders for a while, but the real goal is to be able to edit the DNA of a fully grown adult. Bad genes could be shut off, treating well understood genetic maladies, targeting cancerous cells, and maybe even opening a brave new world of gene modification. All it would take is a shell of a virus stuffed with the genes you wanted to edit and a protein that can help cut DNA in the right places to insert the new code and delete the old one.

This technique is called CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, after a pattern in DNA used to target the therapeutic intervention, and the protein in question is Cas9, which stands for CRISPR-Associated 9. (Yes, some scientific nomenclature is the exact opposite of poetic.) After numerous experiments, CRISPR/Cas9 technology has shown so much promise that it’s slated to start human clinical trials, bringing gene therapy to your doctor’s office in the very near future and possibly saving and improving millions of lives. But it seems that nature is determined to throw us a curveball.

In a pair of studies, researchers found that between 79% and 96% of their test subjects had an aggressive immune response to Cas9, meaning that T-cells in their bodies would destroy the protein before it could cut their DNA and render any therapeutic benefit. While the same sizes were relatively small with just 22 to 48 healthy participants, the strength of this signal is giving scientists pause. It does make sense that our immune system would attack anything foreign, especially something that seeks to modify our genes. That’s why it’s there and why we’d very quickly die without it. But here, it’s working against our best efforts to treat real problems with a clever piece of biological machinery.

Now, all that said, even the fact that even other proteins like Cas9 can trigger a similar immune response this doesn’t mean that we have to back to the drawing board on gene therapy. These proteins are derived from common bacteria our bodies know well and will quickly attack. A new delivery system that minimizes the time for the protein to be active and vulnerable, or hiding it while it does its job in specialized nanoparticles would leave T-cells to clean up after the work is done instead of interfering with the gene edit. These findings are preliminary, through very likely to stand, and despite what they show, this is not catastrophic news. It just means we need to get a little more creative in how we apply the therapy.

See: Wagner, D., et al., High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population, Nature Medicine (2018) DOI: 10.1038/s41591-018-0204-6

Charlesworth, C.T., et al., Identification of Pre-Existing Adaptive Immunity to Cas9 Proteins in Humans, bioRxiv (2018) DOI: 10.1101/243345