Lance Archer, who has lived with sickle cell disease his entire life, works as a patient advocate while serving as a member on the board of directors of the Sickle Cell Awareness Group of Ontario.Nick Iwanyshyn/The Globe and Mail
At 33, Lance Archer has had two hip replacements, is deaf in one ear and lives with severe pain. Mr. Archer has sickle cell disease, a term encompassing a group of inherited blood disorders that predominantly affect Black people. At least 5,000 Canadians live with the condition.
The disease is caused by a genetic mutation that makes red blood cells crescent- or sickle-shaped and sticky, making it difficult for them to move around the body. This can lead to pain crises – agonizing episodes that can result in a trip to the emergency room. Other symptoms include organ damage, stroke and breathing problems. The life expectancy of people with the disease is relatively short.
For Mr. Archer, who lives in Hamilton and was diagnosed at three months old, living with the disease is a constant battle of symptom management that affects every aspect of his life and can make daily tasks a challenge.
“Excruciating pain is a major symptom of the disorder,” he said. “There are nights when it’s really hard.”
Treatment options are limited. Blood transfusions are given to some patients at higher risk of stroke and other severe complications. Stem-cell transplants using donor bone marrow can cure the disease, but it can be exceedingly difficult to find a match.
That could change soon. Two new gene therapies were recently approved for use in the United States. The treatments, Lyfgenia and Casgevy, work so well that many say they represent a possible cure for sickle cell disease and could pave the way for more gene therapies to treat a range of inherited disorders – what some experts say only a few years ago seemed like science fiction.
But the high costs – the list price for Lyfgenia is US$3.1-million, and for Casgevy US$2.2-million – and the complexity of administering the treatments will keep them out of reach of many. And like any invasive treatment, in this case on a genetic level, there are inherent and adjacent risks.
Neither treatment has been approved in Canada, but medical experts and patients say governments and hospitals must urgently address these thorny issues.
“From a practical standpoint, there are so many barriers,” Mr. Archer said. “We have a long way to go in ensuring that this is something that people within the community can access.”
Gene therapy is a broad term that refers to any modification to a person’s genes to treat, cure or possibly even prevent diseases that are genetic in nature. Genes may be edited, added or removed. Disease-causing mutations may be deactivated or genetic modifications introduced to promote a therapeutic benefit.
There are already several gene therapies approved for use in Canada. In October, 2020, Health Canada approved the country’s first-ever gene replacement therapy medication, Luxturna, which is used to treat a rare inherited retinal condition that causes vision loss. In December, 2020, it approved Zolgensma, which is used to treat spinal muscular atrophy, a progressive neurodegenerative condition that, in its more severe forms, leads to death by the age of 2. The treatment, which targets a specific gene and promotes the production of a critical protein, has been found to stop the disease’s progression and even lead to mobility improvements.
When British authorities green-lit Casgevy in November, it became the world’s first approved treatment based on CRISPR-Cas9 gene-editing technology. Gene editing can be done in a number of ways, but CRISPR makes the process faster, easier and cheaper, allowing researchers to experiment with new therapies at a breakneck pace. In basic terms, CRISPR – clustered regularly interspaced short palindromic repeats – works by using a pair of molecular scissors, typically Cas9 (CRISPR-associated protein 9), and an RNA sequence that works as a guide to identify and cut DNA in a specific spot. This allows scientists to delete, add or replace bits of genetic material.
With Lyfgenia, a patient’s blood stem cells are removed and genetically modified with a functional HBB gene to avoid the sickling and clumping problems caused by the patient’s mutation. The altered gene is then delivered back into the patient via a harmless virus through a one-time intravenous stem cell transfusion. In the case of Casgevy, a patient’s blood stem cells are removed, and CRISPR-Cas9 technology is used to edit the gene so that it promotes the production of fetal hemoglobin, which doesn’t succumb to “sickling,” as the patient’s adult hemoglobin does. It, too, is delivered through a one-time infusion.
In a multicentre U.S.-based clinical trial, patients who experienced vaso-occlusive crises, a common complication of sickle cell disease that leads to extreme pain, were treated with Casgevy. After one year, 93.5 per cent of the study participants experienced no subsequent crises.
Both treatments were approved in the U.S. in December but won’t be available to all sickle cell patients right away, as they must be administered at advanced facilities with specially trained staff. This month, a spokesperson for Vertex Pharmaceuticals said the company hopes to submit an application for approval of Casgevy to Health Canada in the near future. A spokesperson for Massachusetts-based Bluebird Bio, which produces Lyfgenia, said the company is focused on the U.S. market and has no immediate plans to bring the therapy to Canada.
Beyond providing the possibility of relief to people in select countries around the world who suffer daily as a result of sickle cell disease, these advancements in gene therapy and the landmark approval of a CRISPR-based treatment represent a watershed moment in medicine that could pave the way for breakthroughs in a host of other genetic conditions.
“What these announcements and headlines mean is, I think, in the next five to 10 years, scientists and researchers and these pharmaceutical companies might be able to actually cure or treat pretty much every single genetic disease where we know the mutation,” said Tyler Wenzel, a postdoctoral fellow at the University of Saskatchewan who uses stem cells to create diagnostic tools and treatments.
In fact, several experts interviewed by The Globe and Mail said that, not long ago, they would have thought a treatment like Casgevy existed only in the distant future.
“Eight to nine years ago, if you would have told me, ‘Don’t you think you can just fix a mutation?’ I would have said, ‘No, I don’t think so,’” said Ronald Cohn, the president and chief executive of Toronto’s Hospital for Sick Children. “The fact we can explore all these things right now, it’s unbelievable.”
Sven Kili, the chief development officer with the Centre for Commercialization of Regenerative Medicine, a non-profit organization that focuses on the commercialization of regenerative medicine, said the possibilities for the future seem endless and could even lead to therapies to prevent the development of a range of diseases.
“That’s really going to be a very exciting component,” Dr. Kili said.
However, in addition to the high costs, some experts worry that the fanfare over the gene therapy revolution overshadows the very real risks of these treatments. People who undergo treatment with Casgevy and other forms of gene therapy often have to contend with extensive hospital stays and high doses of chemotherapy, which can lead to infertility, infections and other health consequences.
“I think that’s not necessarily been emphasized in all the excitement,” said Greg Guilcher, an associate professor of oncology and pediatrics and the program director for the Childhood Cancer and Blood Disorders Research Program at the University of Calgary.
And questions of access and equity are central to the discussion, especially in a country as large as Canada.
“These are brutally expensive therapies,” Dr. Kili said.
And given the complex nature of gene therapy treatments, they will likely only be provided in the most advanced medical facilities in urban centres such as Toronto. So how can patients who live in remote parts of the country access such therapies, especially since they involve lengthy hospital stays?
“Even if you’re in a city like Saskatoon or Regina, we still might not have the facilities required to actually create these types of therapies,” Dr. Wenzel said. “Our patients in Saskatchewan might still have to travel.”
Members of the sickle cell community say anti-Black racism and long-standing issues of discrimination are another barrier patients face. Lanre Tunji-Ajayi, president of the Sickle Cell Awareness Group of Ontario, lost a brother to preventable sickle cell complications in 1998 and says stigma continues to play a major role, keeping the disease in the shadows.
“Many people don’t want to talk about sickle cell because of discrimination,” she said. “There’s still anti-Black racism alive, and that is very clear.”
Ms. Tunji-Ajayi, who also has a sister with sickle cell disease, says it can be difficult for patients to get help when they go to an emergency department in pain. She’s heard many stories of people being dismissed as drug users in search of narcotics.
Carly Weeks