La company who has just obtained approval to market the first gene editing treatment in history to cure sickle cell anemia, is already looking for a common medication that can replace it.
Vertex Pharmaceuticals has a team of 50 people working “to manufacture a pill that does not perform any type of gene editing,” says David Altshuler, head of Research at the Boston pharmaceutical company.
“We are trying to innovate more than ourselves,” Altshuler announces.
On December 8th, Vertex obtained approval in the US to sell the world’s first treatment using CRISPR, the gene editing technique. Its development has lasted eight years and has involved a large financial investment. Regulatory documents submitted to the government during the approval process exceeded one million pages.
However, now that the CRISPR era of medicine has begun, some of the limitations of the technique are already visible.
The Casgevy treatment is harsh for patients and very expensive. Patients must spend several weeks in the hospital while doctors remove, genetically modify, and reintroduce their blood-producing bone marrow stem cells. According to Vertex, the treatment will cost 2.2 million dollars (2 million euros), not including hospital expenses.
Vertex has shown that genetic correction can be a permanent remedy for people suffering from the most severe symptoms of sickle cell anemia. These patients, estimated to be about 16,000 in the EU, suffer from painful recurrent crises when deformed red blood cells block their blood vessels.
However, it is not clear how many Americans will opt for gene editing. In an opinion column for the MIT Technology Review, Jimi Olaghere, a patient who received the treatment, stated that bone marrow replacement is an “intense months-long journey” and will create access barriers.
Previously, several gene therapies have failed in the market due to a combination of high prices and very few patients.
“It is a miracle, but it also has a drawback that prevents widespread use,” says Geoffrey von Maltzahn, partner at Flagship Pioneering, which runs biotechnology companies but did not participate in the sickle cell anemia treatment. “It’s a common duality.”
If a pill is developed to alleviate sickle cell anemia, these drawbacks could sweep CRISPR off the playing field. A pill version could also solve a moral dilemma. Vertex does not plan to offer its gene editing treatment in countries where sickle cell disease is more common.
80% of cases of sickle cell anemia occur in a wide range of low-income countries in Central Africa, such as Nigeria and Ghana. But, according to US researchers, they lack hospitals, medical expertise, and funding to carry out this complex intervention.
“A question I am often asked is: How are we going to reach the rest of the world?” Altshuler explains. “I think the answer is not to try to do bone marrow transplants in the rest of the world, because it requires too many resources and the necessary infrastructure does not exist. I think the goal will be achieved more quickly by seeking another modality, such as a pill that can be distributed more effectively.”
Three strategies
In an interview with the MIT Technology Review, Altshuler outlined three ideas that Vertex is exploring to improve its innovative CRISPR treatment.
One of them is to replace the intense chemotherapy used to destroy a person’s bone marrow and make room for edited cells to take over. Vertex and other gene editing companies, such as Beam Therapeutics, claim to be studying gentler methods that could make the procedure easier for patients.
The second idea that Vertex and other companies are exploring is called in vivo editing. In this case, gene editing molecules are administered by drip into the patient’s vein, or even injected like a vaccine, without the need for a transplant.
To achieve in vivo editing of blood diseases, research groups are trying to develop targeting systems -viruses or special nanoparticles- that deliver CRISPR directly to a person’s hematopoietic stem cells. The Bill and Melinda Gates Foundation considers that this could help solve the problems of sickle cell anemia and HIV in Africa, and has supported these “one-time” editing treatments. But it is still in the experimental phase, and some experts wonder if this will ever be possible.
The last idea is a conventional drug, an oral solution would be the easiest to distribute where it is needed. Angela Koehler, a biochemist at MIT, says that “widely accessible” drugs with “low access barriers” would have the greatest impact on sickle cell anemia worldwide.
“This does not diminish my enthusiasm for CRISPR-based approaches, but explains the motivations of researchers trying to develop ‘traditional’ drugs,” Koehler admits.
Continuing to innovate
Sickle cell anemia is caused by defects in hemoglobin, the molecule in red blood cells that carries oxygen. CRISPR treatment stops the worst symptoms of the disease through selective DNA editing that activates fetal hemoglobin, a second version that any human has but remains inactive at birth.
In early 2019, according to Altshuler, he already saw the results of the first genetically modified patients who volunteered for the company’s trial. At that time, the theory was confirmed that creating fetal hemoglobin could be a treatment.
A few weeks after detecting these results, Altshuler claims that he set out to find a conventional drug that could do the same thing, even as the CRISPR program continued. “The goal is to achieve a similar profile with a pill instead of gene editing,” he says.
Reaching everyone with a treatment was part of the motivation, but not the only one. Vertex was also driven by a painful lesson it learned after launching Incivek, its innovative drug against hepatitis C in 2011. At that time, the drug recorded the fastest sales increase in history for any product, reaching 1.5 billion dollars (1.4 billion euros) in a year.
However, three years later, Vertex had to stop marketing Incivek after its competitor Gilead Sciences presented a more effective and less side-effect drug.
The harsh lesson was to continue innovating.
“I have never understood something about biopharmaceuticals: they discover the first drug for a disease and let others eat their lunch,” admits Altshuler. “They stop researching and wait.”
In search of the pill
The search for the pill remains surrounded by secrecy. Altshuler does not want to reveal any details and claims that the lack of public information is part of the appeal of the project.
However, it may be that Vertex’s search focuses on the same biological target that CRISPR modifies. This is the BCL11A gene that acts as a switch that controls fetal hemoglobin. Gene editing deactivates that gene, allowing fetal hemoglobin to increase.
It is not easy to get an ordinary drug to mimic that effect. The difficult part is that the BCL11A gene produces a transcription factor, a type of flexible and deformable protein that lacks the specific folds and vertices that chemists can target with drugs. In fact, these molecules are known to be “difficult to treat.”
According to Altshuler, currently no marketed drug works by binding to a transcription factor.
Although the search for a drug has been discreet and gone unnoticed so far, clues have already begun to emerge, including from other companies pursuing similar goals. This week, at a major meeting on blood disorders, the pharmaceutical company Novartis reported that it had analyzed several thousand molecules and found some capable of increasing fetal hemoglobin.
On the other hand, at the same meeting, a team at Boston Children’s Hospital indicated that they had discovered how the BCL11A protein folds. This highlights possible ways that drugs could act on it.
This laboratory is headed by Stuart Orkin, a scientist whose discoveries on the fetal hemoglobin switch we recently featured in the MIT Technology Review. “There are those who try to find new targets, but I don’t think there is anything else worth studying,” Orkin says. “It is the only one that will lead us to a solution.”
Orkin explains that he has also been looking for a drug, but that those attempts, some in collaboration with Koehler, have not yet yielded results. “I can say that we have tried many things that do not work,” he says.
Orkin believes that gene editing will become a better treatment, if it can be achieved. “If I had a child and could choose between a cure or taking pills for life, I would opt for editing. If it can be cured, I would,” he concludes. “But many patients are not ready for the rigor of a transplant and many are not in an environment where it can be done. There are not enough hospitals or doctors.”
That is the irony of the first CRISPR treatment. It can cure patients, but it still cannot overcome a disease. In fact, the problem of sickle cell disease is only growing. This is because countries with high rates of this hereditary disease also have large populations. Every year, more people, not fewer, suffer from this disease. CRISPR still cannot reverse that trend, but a pill could.
“It is solved from the disease point of view, but not from the mortality side,” Orkin concludes. “That’s the next chapter. Sickle cell disease is a big problem and it is growing, not shrinking.”
1703032585
#Vertex #desarrollado #una #cura #CRISPR #pero #busca #paso #más #allá
2023-12-19 23:26:09
