Gene therapy is finally upon us. After more than two decades of work, one product is approved in Europe. Others are steadily advancing through clinical trials, and gene therapy companies are doing big deals and raising big sums of cash.
Now here comes a more precise version of gene therapy—gene editing. Instead of trying to insert a correct version of a faulty or missing gene as in gene therapy, the idea behind gene editing is to actually snip out the faulty genes that cause disease, and perhaps even replace them with new, improved versions.
Editing genes, not just adding genes, could be a huge help with the rare inherited Li-Fraumeni Syndrome, says Robert Lufkin, an oncologist in Portland, OR, and advisor to the Li-Fraumeni Syndrome Association. Li-Fraumeni, which causes cancer in childhood or early adulthood, and with multiple types of cancer, stems from a mutation in a gene called p53 that normally suppresses tumor growth. But adding a healthy version of p53 isn’t necessarily the answer, because accumulation of the mutated version has its own problems. “I am hopeful that someday a form of genome editing may be used in severe genetic disorders” like Li-Fraumeni, says Lufkin.
My colleagues and I write frequently about the promising technologies that are making gene editing possible, such as zinc fingers and CRISPR/Cas9.
In particular, CRISPR/Cas9 already has caught on around the world as a research tool to cut out or replace genes in organisms from bacteria to wheat to mice to monkeys. Work in human cells is starting to emerge, too. Derived from a bacterial defense system, CRISPR/Cas9 is a potential Nobel-winning biotech discovery. (CRISPR stands for clustered regularly interspaced short palindromic repeats; Cas9 for CRISPR-associated protein 9.)
A few companies are racing to make gene-editing therapies. With its proprietary zinc finger technology, Richmond, CA-based Sangamo Biosciences (NASDAQ: [[ticker:SGMO]])) is the first (and only) company to reach clinical trials: It’s now running a Phase 2 trial in HIV and has just been greenlighted by the FDA to begin clinical trials in beta thalassemia.
(A third gene editing system, known by the acronym TALEN, has yet to generate the widespread use of CRISPR/Cas9 or the clinical progress of zinc fingers, although French TALEN developer Cellectis inked a deal with Pfizer (NYSE: [[ticker:PFE]]) last December.)
Before it can be a successful treatment or cure, however, gene editing must solve a thorny problem: How to ensure that the edits in DNA are made in the right spots? Go off target, and the genetic manipulation could have serious consequences. The history of gene therapy offers cautionary tales of genetic engineering gone awry, such as the unexpected trigger of leukemia in a French trial for X-linked severe combined immune deficiency disorder (the “bubble boy disease”), and the death of Jesse Gelsinger from an immune system reaction in Philadelphia in 1999.
But now comes progress in the effort to build a system of quality control for gene editing. In the past two months, three academic groups have published papers—all in Nature Biotechnology—describing new ways to measure the frequency and location of off-target cuts in cells’ DNA. A review in this month’s issue covers all three papers, and the reviewers laud them for moving the field forward: “The new studies are a major step toward clinical applications of genome engineering as they show that sensitive, genome-scale detection of nuclease activity is now technically feasible.” (Nucleases are the “scissors” that gene editing systems use to cut DNA.)
That sensitive detection is important, because it’s virtually inevitable that the gene-editing tools will go off target. The goal is to know quickly when, where, and how frequently, and use those data to adjust the technology in certain diseases or patient groups—or steer clear of them entirely.
Take CRISPR/Cas9. The system uses two main components: an enzyme called a nuclease to cut DNA, and a strand of RNA that acts as the nuclease’s guide by matching up with the segment of DNA the enzyme is meant to cut. The beauty of CRISPR/Cas9 is that for most uses, the scissors stay the same. Only the guide needs to be swapped out, a relatively simple exercise in many biomedical labs these days.
That’s why it has caught on so rapidly. “You can make hundreds of these things trivially,” says Jacob Corn, scientific director of the new Innovative Genomics Initiative, jointly run by the University of California, Berkeley, and the University of California, San Francisco. Experiments that used to take
