The gene editor CRISPR won’t fully fix sick people anytime soon. Here’s why
This week, scientists will gather in Washington, D.C., for an annual meeting devoted to gene therapy—a long-struggling field that has clawed its way back to respectability with a string of promising results in small clinical trials. Now, many believe the powerful new gene-editing technology known as CRISPR will add to gene therapy’s newfound momentum. But is CRISPR really ready for prime time? Science explores the promise—and peril—of the new technology.
How does CRISPR work?
Traditional gene therapy works via a relatively brute-force method of gene transfer. A harmless virus, or some other form of so-called vector, ferries a good copy of a gene into cells that can compensate for a defective gene that is causing disease. But CRISPR can fix the flawed gene directly, by snipping out bad DNA and replacing it with the correct sequence. In principle, that should work much better than adding a new gene because it eliminates the risk that a foreign gene will land in the wrong place in a cell's genome and turn on a cancer gene. And a CRISPR-repaired gene will be under the control of that gene’s natural promoter, so the cell won’t make too much or too little of its protein product.
What has CRISPR accomplished so far?
Researchers have published successes with using CRISPR to treat animals with an inherited liver disease and muscular dystrophy, and there will be more such preclinical reports at this week’s annual meeting of the American Society of Gene and Cell Therapy (ASGCT). The buzz around CRISPR is growing. This year’s meeting includes 93 abstracts on CRISPR (of 768 total), compared with only 33 last year. What’s more, investors are flocking to CRISPR. Three startups, Editas Medicine, Intellia Therapeutics, and CRISPR Therapeutics, have already attracted hundreds of millions of dollars.
So why isn’t CRISPR ready for prime time?
CRISPR still has a long way to go before it can be used safely and effectively to repair—not just disrupt—genes in people. That is particularly true for most diseases, such as muscular dystrophy and cystic fibrosis, which require correcting genes in a living person because if the cells were first removed and repaired then put back, too few would survive. And the need to treat cells inside the body means gene editing faces many of the same delivery challenges as gene transfer—researchers must devise efficient ways to get a working CRISPR into specific tissues in a person, for example.
CRISPR also poses its own safety risks. Most often mentioned is that the Cas9 enzyme that CRISPR uses to cleave DNA at a specific location could also make cuts where it’s not intended to, potentially causing cancer.HT: SeeItMarket
With these caveats, do you even need CRISPR?
Conventional gene addition treatments for some diseases are so far along that it may not make sense to start over with CRISPR. In Europe, where one gene therapy is already approved for use for a rare metabolic disorder, regulators are poised to approve a second for an immune disorder known as adenosine deaminase–severe combined immunodeficiency (SCID). And in the United States, a company this year expects to seek approval for a gene transfer treatment for a childhood blindness disease called Leber congenital amaurosis (LCA).
At the ASCGT meeting, researchers working with the company Bluebird Bio will present interim data for a late-stage trial showing that gene addition can halt the progression of cerebral adrenoleukodystrophy, a devastating childhood neurological disease. Final results could help pave the way for regulatory approval. Bluebird will also report on trials using gene transfer for two blood disorders, sickle cell disease and β-thalassemia, bringing these treatments closer to the clinic.
Except for LCA, in which gene-carrying viruses are injected directly into eyes, these diseases are treated by removing bone marrow cells from patients, adding a gene to the cells, and reinfusing the cells back into the patient. New, safer viral vectors have reduced risks of leukemia seen in a few patients in some early trials for immunodeficiency diseases. Researchers are seeing “excellent clinical responses,” says Donald Kohn of the University of California, Los Angeles.
Although Kohn and other researchers have used an older gene-editing tool known as zinc finger nucleases to repair defective genes causing sickle cell disease and a type of SCID in cells in a dish, only a tiny fraction of immature blood cells needed for the therapy to work end up with the gene corrected—far below the fraction altered by now standard gene transfer methods. One reason is because the primitive blood cells aren’t dividing much (more on this below). Because gene-editing methods such as CRISPR are so much less efficient than gene addition, for several diseases, “I don’t think there will be a strong rationale for switching to editing,” says Luigi Naldini of the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.
CRISPR also has other issues
Using CRISPR to cut out part of a gene—not correct the sequence—is relatively easy to do. In fact, this strategy is already being tested with zinc finger nucleases in a clinical effort to stop HIV infection. In this treatment, the nucleases are used to knock out a gene for a receptor called CCR5 in blood cells that HIV uses to get into cells....MORE