By Alice Park
August 6, 2019

It’s only been seven years since scientists first learned how to precisely and reliably splice the human genome using a tool called CRISPR, making it possible to think about snipping out disease-causing mutations and actually cure, once and for all, genetic diseases ranging from sickle cell anemia to certain types of cancer and even blindness.

Doctors are plunging ahead in search of ways to use the relatively new technology to start treating patients. In China last November, scientist Jiankui He stunned—and dismayed—the genetic community when he announced he had already used CRISPR, which many believe still hasn’t been proven either safe or effective in human patients, to permanently alter the genomes of twin girls to be immune to HIV infection. He’s experiment was criticized because he edited the twins’ cells when they were embryos, therefore ensuring that every one of their cells is now changed, including their reproductive ones, which means their edited genomes can be passed on to their children, despite the fact that experts can’t be sure what the long term effects of such lasting modifications might be.

Editas Medicine and Allergan recently announced a more acceptable form of gene editing, one that would change genetic defects in cells that don’t get passed onto the next generation. They are enrolling patients born with a congenital vision disease into what will be the first test in the U.S. of whether CRISPR can fix a mutation in the cells of a living human body. Other ongoing trials, including one from partners Vertex Pharmaceuticals and CRISPR Therapeutics that is treating blood diseases, rely on treating patients’ cells outside of their body and introducing them back to the body, where, in theory, they would outnumber the diseased cells.

In the Editas study, CRISPR will be introduced directly into the eye where it will repair the genetic mutations in the patients’ vision cells and potentially cure them of their disease. The illness, called Leber congenital amaurosis 10 (LCA10), is caused by a single mutation in the CEP290 gene, which is critical for building the outer portion of photoreceptor cells that sense and translate light into signals that travel through the optic nerve and into the brain where they are interpreted as sight. The mutation prevents the photoreceptors from sensing light, which contributes to low vision or blindness.

The fact that LCA10 is a single-gene disease make it an ideal target for early CRISPR therapies. Scientists can design CRISPR to act as molecular scissors to snip a cell’s DNA in specific, pre-determined locations — in this case around the aberrant CEP290 gene — and remove it. Without the mutation, the normal protein can be made and the photoreceptor cells can function as they should.

“We are going in and cutting out the mutation,” says Charles Albright, chief scientific officer of Editas. “Hopefully that will restore the normal protein to normal levels and let patients sense light again, and that sensation of light can turn into vision.”

Scientists agree that CRISPR holds great promise in giving researchers unprecedented power to snip out abnormal stretches of DNA, But there are still significant questions about how safe and effective CRISPR gene editing will be once it’s unleashed in the human body. CRISPR works well enough in the lab, in a dish of human cells, but as with any technology, there are glitches. Some studies have shown that the gene editing goes awry once in a while, splicing incorrect places in the genome. Then there is the bigger question of what longer term, unanticipated effects man-made edits to the human genome might have.

But, if the CRISPR gene editing works, it would be a one-time fix for a genetic disorder that currently can’t be treated at all. “This is a super cool idea, and it has a ton of potential,” says Dr. Steven Schwartz, professor of ophthalmology at the University of California Los Angeles Stein Eye Institute, who is not involved in the study. The genetic editing would essentially eliminate the genetic mutation that these people had been born with, and depending on how early the treatment is given, could not only restore, but possibly preserve their vision. Some children with the condition are born with limited sight and eventually go blind, so Editas and Allergan plan to eventually include children as young as three years old in the study if the first doses appear safe.

The trial will hopefully answer many questions could be critical for the future of CRISPR-based therapies. Studying the technique in patients will give doctors clearer answers about dosing the therapy, as well as potential side effects. Albright says the treatment will be provided during outpatient surgery, in which the surgeon will inject the molecular gene editing machinery under the retina. The CRISPR mechanics will be encased in a deactivated adenovirus built specifically to deliver its splicing payload to photoreceptor cells. Even if they unload the CRISPR in other cells, says Albright, it’s not biologically dangerous since the gene is only mis-coded in the photoreceptor cells.

To track if the CRISPR did its job, the research team will assess the patients’ vision with a special test designed for those with low vision, and will record video of the patients working through a maze in which they have to avoid obstacles and heed instructions such as stop signs. The scientsits also plan to use imaging to try to track whether the photoreceptors cells have actually been rebuilt.

Learning From Human Studies

The trial is just one of a few underway to test the powerful CRISPR technology around the world. One of the most promising, for example, is studying whether gene editing can treat, and effectively cure, blood disorders such as beta thalassemia and sickle cell anemia.

In beta thalassemia, the hemoglobin part of red blood cells, which is supposed to pick up oxygen from the lungs and distribute it to the cells in the rest of the body, doesn’t work properly. Patients need to be transfused with donors blood regularly, and even with these transfusions, complications can occur if the dose isn’t right and iron levels in the blood cells spike, which can lead to organ damage and even death. In sickle cell disease, a mutation in the gene that makes hemoglobin causes the red blood cells to collapse into a sickle shape, which makes it more difficult for the cells to flow smoothly through the body’s arteries and veins. Blockages caused by the misshapen blood cells can lead to severe pain and strokes.

The biotech company CRISPR Therapeutics, founded by one of the technology’s co-developers, has engineered a solution to treat both conditions that relies on genetic modifications connected to the production of fetal hemoglobin. Normally fetal hemoglobin, which provides the developing fetus with oxygen via the blood while in utero, is shut off about six months after birth, and genes for adult hemoglobin are turned on. While it’s not clear why adult hemoglobin replaces the fetal version, researchers say that they have not seen any significant differences between the two types when it comes to the ability to transport oxygen to the body’s cells. However, since the genes for adult hemoglobin don’t produce healthy red blood cells in people with beta thalassemia and sickle cell disease, one treatment strategy is to introduce genetic changes that turn on fetal hemoglobin again.

In CRISPR Therapeutics’ trials for each disease, doctors remove patients’ bone marrow cells, which contain the stem cells that make all blood cells, treat these stem cells outside of the body with CRISPR to turn on the fetal hemoglobin genes, then give patients strong chemotherapy to remove their existing, diseased bone marrow stem cells and replace them with the CRISPR-edited cells. Because these cells are now altered to make fetal hemoglobin, hemoglobin levels eventually rise back to normal levels for beta thalassemia patients, and the red blood cells now have a normal shape in those with sickle cell.

For people with beta thalassemia, the gene editing therapy could mean the end to a lifetime of transfusions, and for sickle cell patients, a first-ever treatment. “When we make this change [with gene editing], the notion is that this is a transformative, one-time cure for life for these diseases,” says Samarth Kulkarni, CEO of CRISPR Therapeutics.

Kulkarni won’t reveal much about how far along the trials are, but says that the first patient with beta thalassemia who was treated with CRISPR has not needed transfusions in four months. He hopes to enroll 45 people in this first study of the gene editing treatment for each disease, but plans to review the safety of the therapy after the first 17 people have been treated. The preliminary results “are an encouraging sign,” he says. “But these are early days still.” Early, but promising.

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