Powerful new tools could turbocharge gene replacement therapies, but questions over ethics, safety and costs remain. Two clinics sit adjacent to one another in a new hospital in a medium-sized city in the developed world.
In one, a family waits for a long-scheduled appointment. Their daughter suffers from a rare inherited disease. One of her genes encodes for a protein that doesn’t perform its functions normally, and her degenerative ailment is most likely fatal. Their doctor is about to discuss a procedure that will remove cells from the affected organ, correct the inherited faults and reinfuse her cells, allowing her organ to perform its functions without the inborn errors that she and her family have been managing since her birth.
The procedure is expensive, requiring a payment plan over a decade financed by a start-up, and it will need chemotherapy and a hospital stay. But it’s a one-time fix, and if side-effects appear down the line, doctors will study them.
In another waiting room, a soon-to-be-expectant couple waits to meet a geneticist. The doctor will present a plan for their unborn baby: to alter a few lines of its DNA to reverse a rare disorder before it even starts and prevent it from being passed to their grandchildren. Both parents carry the recessive gene that causes the disease, but because of the opportunity to correct it after fertilisation, they decide to try to get pregnant. It’s supercharged IVF.
Both of these scenarios are cutting-edge and experimental.
The first is being tried around the world and has seen some breathtaking achievements. In the United States, more than two dozen such gene-editing therapies have been approved to tackle blindness, rare immune and genetic disorders, and some cancers. But they remain expensive and tailored to the very, very few.
The second has been condemned. In-embryo edits – changes that would be replicated into reproductive cells and passed to future generations – are banned by many governments.
But either, or both, could become more common in the coming years. In March, scientists, genetics entrepreneurs, ethicists and policymakers pondered the future of the sector at the third International Summit of Human Genome Editing at the Royal Society in London.
It was on the same stage that a scientific scandal hit global headlines in 2018 when Chinese geneticist He Jiankui announced he had altered the DNA of the embryos of twin girls to protect them from an HIV infection in the future. He brought the embryos to term, was called “Dr Frankenstein” by some and sentenced to three years in prison by a Chinese court.
His revelation served as a curtain-raiser to a new era in which the codes that make our bodies can be edited. Work to correct genetic diseases has continued bounding forward.
So what’s next in the field of gene editing? Could it eliminate rare diseases previously believed to be almost incurable? And how safe will such treatments be?
The short answer: Although some gene-editing therapies are already available, a new generation of tools could turbocharge the search for cures to inherited diseases. But making gene-editing treatments affordable and accessible to more than a few patients remains a challenge, and critical ethical and safety-related questions still need answers.
Victoria Gray, shown in this photo in 2019 at the Sarah Cannon Research Institute in Nashville, Tennessee, where she was treated with a CRISPR-enabled gene therapy for sickle cell disease as part of a clinical trial [File: Sarah Cannon Research Institute /AFP]
The coming ‘cures’
Hundreds of new trials to correct faults in the human genome are under way. Victoria Gray, who stood before the assembled scientists and policymakers in London last month to tell her story, is among the first people ever to have been effectively “cured” of sickle cell anaemia. This genetic disease affects millions of people in the world, mostly in Africa and the United States.
The disease emerges from a single mutation in the human DNA and can shorten life expectancy by decades. Therapies for sickle cell disease have not progressed much in years, and patients still look to painkillers, antibiotics and dietary supplements to manage their pain. The first “cure” by genome editing is expected to be approved by the US Food and Drug Administration in the next several months. Gray had participated in a clinical trial for this treatment.
It will join a growing number of radical new treatments for serious and rare diseases, but these therapies often cost millions of dollars and bring unknown risks that healthcare systems are only just beginning to contemplate.
Fyodor Urnov leads a research centre in Berkeley, California, called the Innovative Genomics Institute. Its scientists are developing treatments for dozens of such illnesses that were until recently thought to be only manageable, including genetic degenerative blindness, blood disorders that slow the body’s ability to nourish itself and inherited cystic fibrosis that blocks the functioning of the lungs.
The institute uses CRISPR, a genomic editing tool that combines genetic fragments with powerful proteins to find and alter targets on the human genome precisely.
Urnov said he is optimistic that he and other researchers will soon treat the rarest of diseases, yet he maintains a pragmatic, almost cautious approach to deploying these cutting-edge tools.
“I don’t want to simplify things too much. Building a clinic-grade CRISPR [medicine] is a lot of work,” he told Al Jazeera. “But it’s not five years.”
He believes it is coming sooner – despite the challenges.
“In the US, a company recently stopped a [gene therapy drug] trial because there were only 300 patients in [the trial],” he said in an interview via Zoom. “Well, that’s unfortunate, but what should we do for a disease that has 20 people in it?”
Twenty people is not a profitable goal for a large biotech company, but it’s exactly the type of challenge Urnov’s group aspires to meet. He envisions a treatment protocol for rare, serious diseases that can be prepared for individual children.
“Our vision, our dream is [that in] major teaching hospitals … there would be a CRISPR cure centre where physicians would see a child,” he said. “The child’s DNA would be read, professional geneticists would see what causes that disease and [the] CRISPR cures group would be like a rapid response team. They would jump on it.”
Jennifer Doudna, a professor at the University of California in Berkeley and co-inventor of the CRISPR gene-editing tool, received the 2020 Nobel Prize in chemistry with Emmanuelle Charpentier for genome editing [File: Susan Walsh/AP)
‘You cannot unedit’
This vision is not yet reality and won’t be until several technological and regulatory hurdles are crossed.
Not all genetically inherited diseases can be attacked equally. Sickle cell anaemia lurks in the bone marrow, where red blood cells are made. The patient’s bone marrow can be removed, its cells edited, the remaining cells cleared and corrected stem cells replenished into the body. Blindness in retina cells in the eye can be reached by eye injection (and eventually even an eye drop).
But reaching cells in the brain or in muscle is more challenging although progress is being made quickly. And while most gene therapies have been delivered by modified viruses, which are machines tuned by evolution to find and alter a host’s genome, new methods of delivery by small particles are on the horizon.
Gene therapies require a rethink of the role of medicine. Most are one-time infusions or extractions that alter the way a body makes cells, and they last for a lifetime. “This keeps us all awake at night,” Urnov said. “Once you have edited someone, you cannot unedit them.”
This is why Urnov and many other researchers insist that genetic intervention therapies must be reserved for very specific conditions. “CRISPR is not ready to treat chronic conditions that currently can be managed with existing medication,” he said. “The place for CRISPR is … a devastating disease for which there are no therapeutic options.”
Urnov said the “longest window of time” through which people who have received CRISPR interventions have been observed is just over three years. “Is it possible that three years from now that person will develop something? It is,” he said. Patients who receive the newest generations of genetic therapies will likely be monitored by doctors for decades.
There are other ethical issues at play too.
The highest burden of sickle cell disease, for instance, is in Africa, which is also where the newest treatments are likely to arrive last. Melissa Creary, a bioethicist at the University of Michigan, studies equity and ethics through the lens of this disease.
“People are open to the promise of the technology of gene editing, but there’s still scepticism for some because we don’t know longitudinally what it means for people who live with sickle cell disease to go through this process,” she said.
That concern comes in part from a history of discriminatory healthcare practices.
Kendric Comer, a 10-year-old sickle cell patient at Children’s National Hospital in Washington, DC, celebrates during a baseball game on World Sickle Cell Day
Source: [Kevin Wolf/AP]
