Slowly but surely, researchers are trying to bring the concept of gene editing closer to clinical reality. Still, no one is saying that this therapy would be commercially available any time soon. Use of gene editing on humans is just beginning to enter clinical trials. At this point, research is focusing only on a small number of diseases that affect relatively small populations.
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More than 3000 diseases have been linked to mutations in individual genes, but researchers are starting with diseases that are most likely to yield positive results. These include HIV and diseases that involve a defect in only one gene, such as hemophilia, sickle cell disease, and beta thalassemia. Meanwhile, "there are many diseases that we are not looking at, such as heart disease, because they have contributions from multiple genes," Dr Urnov says.
Gene editing—more properly called "genome editing"—involves removing and adding specific bits of DNA in a patient's genome. The process is a lot like cutting and pasting words, which is why the process is called "editing." Sangamo's zinc-finger nucleases are engineered from natural enzymes and introduced into the blood, or into the brain or other organs. They can also be used outside the body on stem cells or T cells, which are then introduced into the body.
The zinc finger is able to locate a particular set of defective genes, make a break in the DNA strands there, and introduce new bits of DNA to take their place. "The beauty of this is that we can rely on a natural process to repair the break," Dr Urnov says. "We let Mother Nature do its work."
Dr Urnov says this process has become much more than just a concept. It has been shown to work on mice and other animals in research labs and is now beginning to be used in clinical trials. Sangamo is already in mid-stage clinical trials for HIV and is hoping to get approval for trials on beta thalassemia, sickle cell disease, and hemophilia...
The zinc-finger method was developed almost 20 years ago, but Dr Urnov says research on it only began to hit its stride in 2005, when it was first used to correct a mutant gene in human cells. In the next 3 years, zinc fingers were successfully used to add a whole gene to a specific place in the DNA and then to remove a specific gene, he says...
Recently, however, interest in gene editing has begun to include a rival method to zinc fingers, called "clustered regularly interspaced short palindromic repeats" (CRISPR). Developed just 3 years ago, CRISPR has been hailed as a gene-editing wunderkind by the New York Times, the Wall Street Journal, and the New Yorker.
Despite an ongoing battle over the patent for CRISPR, the technique is beginning to attract substantial investments. In November 2014, Intellia Therapeutics announced a $15 million funding round led by Novartis and Atlas Venture to develop CRISPR...
For all of its merits, however, CRISPR isn't as accurate as zinc fingers in locating specific DNA strands, Dr Urnov and many others contend. "For this reason, it will be difficult to develop as a therapeutic technology," Dr Urnov says...
Beta thalassemia is a blood disorder that reduces the production of hemoglobin, requiring lifetime blood transfusions. Sickle cell disease causes red blood cells to become misshapen and break down, decreasing the amount of oxygen in the blood. Patients with sickle cell disease need to have blood transfusions, iron chelation therapy, and other treatments and medications.
Gene editing for both diseases involves the clever idea of switching from the adult hemoglobin gene, which has been malfunctioning, to the fetal hemoglobin gene, which is in good shape. So it's a switch that would, in effect, cure the patient of the disease. Why are there two genes? The fetal hemoglobin gene is used in the womb when the fetus is taking oxygen from the mother's bloodstream. At birth, it's turned off and the adult gene is turned on. Already, in preclinical research in mice, it has been shown that gene editing with zinc fingers can turn the fetal gene back on, Dr Urnov says...
Dr Urnov says Sangamo is also looking into the use of gene editing for lysosomal storage disorders, such as Hurler and Hunter syndromes. These diseases involve defects of the lysosomes, which act as recycling sites in cells, breaking down unwanted material into simple products for the cell to use to build new materials, and currently there are no cures. Company officials say Sangamo plans to file an IND application with the FDA for Hurler syndrome by the end of 2015 and for Hunter syndrome in the first half of 2016...
Dr Urnov and most other researchers are exclusively using gene editing on somatic cells—cells that aren't involved in the reproductive process and thus will disappear with the death of their host. But there has been some talk about using gene editing for the germline—cells that will be passed on to succeeding generations. Many scientists aren't comfortable with this sort of research, because no one knows what sort of side effects gene editing might produce. If they entered the germline, they might be passed down to future generations.
In March, Dr Urnov and other Sangamo representatives wrote an opinion piece in Nature calling for a moratorium on editing the germline. Also that month, some scientists involved in the CRISPR technology made basically the same plea. These scientists will further discuss the issue in a meeting in December. Although the United States doesn't directly ban it, the National Institutes of Health won't fund human embryo research.
Dr Urnov is concerned that if the scientific community doesn't act against embryo research, authorities might move to ban all kinds of gene editing, including research on somatic cells that could be potentially life-changing for patients with some of these genetic diseases.
http://www.medscape.com/viewarticle/856498_5
See Genetic engineering 11/9/15
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