Chapter 118
Curing Rare Diseases — 7
Virtually every substance we’ve ever put into a person, including just about every medicine we’ve ever put into a person, has off-target effects, meaning [the substance] modulates the function of biological molecules other than the intended target. Of course, the stakes are higher when those are gene editing agents because those modifications can be permanent. I think most off-target edits are very likely to have no consequence because most of our genome, if you mutate in the kinds of small ways—like making an individual base pair change for a base editor—are likely to have no consequence. We sort of already know this because we can measure the mutational burden that we all face as a function of living and it’s measurable, it’s low, but measurable. I’ve read some papers that estimate that there are roughly thirty-seven trillion cells in an adult person, that there are billions and possibly hundreds of billions of mutations that accumulate every day in those thirty-seven trillion cells. So, our genomes are not quite the static vaults that we’d like to think that they are. And of course, we have already purposefully given life extending medicines to patients that work primarily by randomly mutating their genomes. These are chemotherapeutic agents that we give to cancer patients.
In engineering T cells with CRISPR-Cas9 for cancer therapy, extra or missing chromosomes appeared early almost 10 percent of the time. Could we be promoting cancer? When CRISPR-Cas9 was coupled with an adeno-associated virus vector, insertions of pieces of the virus genome were found in the T cells. Yet another worry is unintended editing that takes place in a person’s ovaries or testes, as has been noted in nonhuman primates, which could potentially lead to germline transmission of renegade DNA in eggs or sperm. Meaning, we would pass along the negative consequences to our kids. And their kids.
It’s not just the cut and nick DNA edits that are the worry. There are potential reactions to what the editor and guide RNA are packaged in. An immune reaction to an adenovirus-associated virus vector used in CRISPR genome editing of a patient with Duchenne muscular dystrophy was implicated as the cause of death, the first patient to die after genome editing.
For ex vivo editing used for the approved treatments of sickle cell disease and beta-thalassemia, the patient must undergo busulfan therapy that wipes out the bone marrow in order to make room for the edited blood stem cells. That chemotherapy comes with downstream risk of cancer. It is unsurprising that the FDA has warned on the possible risks of cancer with gene therapy for engineered T cells, and this caution should extend to all forms of genome editing too. Long-term surveillance is needed alongside mitigating these risks, with better editors and delivery methods. While prime editing is currently considered the most versatile form, its efficiency has been shown to be markedly enhanced.