By Merlin Crossley, UNSW
SYDNEY, Dec 19 – A new gene therapy has just been approved as a treatment for the inherited blood disease, sickle cell disease, in the United Kingdom and the United States.
What makes this therapy unique is that it uses a gene-editing technology known as CRISPR, which allows for precise and efficient editing of the genetic code.
But this doesn’t mean human gene modification is about to go viral.
Rather, this is a safe and sensible technology that has the power to help the 300,000 babies born with sickle cell disease each year and the nearly 10 million people estimated to suffer from this genetic disorder globally.
That’s if patients can access the treatment and if ways are found to cover the high up-front costs of more than USD$2 million per patient.
CRISPR is one of the latest big things in DNA research, since it emerged just over a decade ago.
Scientists realised that DNA was a double helix in the 1950s, they could read or sequence genes by the 1970s, and now we are using CRISPR to actually write the genetic code.
However, don’t expect designer babies or an attack of the clones anytime soon.
Sickle cell disease is caused by a single letter misspelling — think of it like a critical typo — in the gene encoding adult globin, a component of hemoglobin, a molecule found in red blood cells that is important for carrying oxygen to the muscles and tissues throughout your body.
This genetic mutation or misspelling affects the configuration of the adult globin molecules, causing them to stick together and form long chains that can change the shape of red blood cells — making them look like sickles.
The cells block narrow blood vessels and damage tissues — virtually every tissue. Patients suffer from pain and eventual organ failure.
While the symptoms of sickle cell disease can be managed in part through various medications, via blood transfusions, and in some cases by bone marrow transplants from matched siblings, limitations in the feasibility and efficacy of these treatments meant that scientists have continued to search for a proper cure.
First generation CRISPR technologies — and this is the first — allow us to cut the double helix DNA molecule in whatever location, in any gene or in regions between genes, that we choose.
Then natural DNA repair processes in the cell stitch the ends together, usually making a small deletion, just as tying a knot in a piece of string might.
First generation techniques cannot efficiently correct spelling mistakes, they just make deletions and in effect rub out words.
While this technique couldn’t correct the genetic typo causing sickle cell disease, it addressed the root cause of the disease in another way.
Researchers — and I’m one of them — who had been investigating the biology of globin genes for decades had noted that some people with the sickle cell disease mutation were virtually free of symptoms, because another gene saved them.
They were expressing a ‘super’ globin, fetal globin that binds oxygen tightly and allows babies to draw oxygen from their mother’s blood when in utero.
Usually, this gene is turned off at birth, but a few people keep it on. It can stand in for the mutant adult globin gene. Remarkably, these people are just fine.
They are walking around, living normal lives. They just have a second mutation that stops the ‘super globin’ fetal globin gene from being turned off.
The new therapy mimics the mutations in these people. It involves cutting and destroying one key DNA sequence to keep fetal globin on. So fetal globin does its job and the symptoms of sickle cell disease go away.
If that sounds complicated, that’s because it is.
Instead of correcting the mutation, researchers have knocked out the off-switch of a different gene to turn that gene on, and that super globin is curing the disease. It’s a double negative.
Researchers took this convoluted route for two reasons.
First, sickle cell disease is just one of a hundred or more highly related disorders caused by different mutations that affect the production or function of adult globin.
This approach represents a universal cure — researchers don’t have to design CRISPR strategies to correct all the different mutations.
Second, while, as you may have heard, CRISPR can correct mutations efficiently in the lab, it turns out that making corrections with first generation CRISPR is not very efficient in blood stem cells.
Newer gene-editing approaches are also being developed.
For example, base editing enables some misspellings of the four DNA bases — the chemical building blocks of DNA, adenine, cytosine, guanine and thymine, commonly represented as A, C, G and T respectively — to be corrected but the chemistry of DNA is such that one cannot yet change every letter into every other letter.
Another technique, called prime editing, should be like ‘find and replace’ in a word processing program, but we don’t know if it is efficient enough for gene therapy yet.
Even if it is, that doesn’t mean people will start building brand new people or superhuman soldiers.
The human genome is like a city. Think of the sickle cell disease mutation as a pothole that blocks a road. At present we are fixing the road block by just knocking down a gate, so traffic can get round via an alternative track — the fetal globin route.
Even if base editing and prime editing work, all we’ll be doing is repairing a road here and there.
This therapy involves taking blood stem cells from patients, modifying them, and putting them back.
It’s complicated, that’s why it is an expensive treatment. But families are not changed genetically, there are no mothers carrying mutant embryos. It is ‘opt in’ for the patient. It will occur one patient at a time and cannot ‘go viral’.
Perhaps one day we will have to sit down to discuss human modification, but for now we are fixing potholes that affect the blood of some people.
A small thing for humanity perhaps, but a huge change for those with this lifelong genetic disease.
Merlin Crossley is Deputy Vice-Chancellor of Academic Quality and a professor of molecular biology at UNSW.
Article courtesy of 360info.
