Healing with one's own genes: the silent revolution of gene therapy

A gene therapy has successfully cured a group of nine children, aged between 5 months and 9 years, restoring their immune function and extending their life expectancy thanks to an experimental gene therapy. The children suffered from an extremely rare and potentially fatal genetic disease: severe leukocyte adhesion deficiency type 1 (LAD-1), which affects one in every million people worldwide.

However, there are very few gene therapy studies in the world, acknowledges Julián Sevilla Navarro, a hematologist at the Niño Jesús University Children's Hospital and coordinator in Spain of the study published last week in The New England Journal of Medicine .

The gene therapy developed by researchers from CIEMAT , CIBERER and IIS-FJD consists of introducing a functional copy of the CD18 gene into stem cells to treat LAD-I immunodeficiency.

LAD-I prevents white blood cells from reaching infection sites due to a mutation in the gene encoding the CD18 protein, which is essential for the functioning of the immune system. Without this protein, patients are vulnerable to severe bacterial and fungal infections from the first months of life. Without treatment, survival beyond infancy is rare.

The new gene therapy corrects this genetic defect using the patient's own blood stem cells . These cells are extracted, modified in the laboratory using a lentiviral vector that introduces a functional copy of the CD18 gene, and then reinjected to generate immune cells.

After demonstrating its efficacy in animals, the technology was licensed in 2016 to Rocket Pharma , which conducted an international clinical trial in nine patients, one of them at the Niño Jesús Hospital in Madrid. The therapy, carried out at centers in the US, the UK, and Spain, has shown successful results: all treated patients are alive and free of recurrent infections after 18 to 45 months of follow-up.

Unlike the only treatment currently available, bone marrow transplantation from a compatible donor, which carries risks such as graft-versus-host disease, this gene therapy allows patients to be their own donors, minimizing complications and serious side effects.

" These children are no longer defined by their diagnosis. They're growing, learning, playing... just like any other child with a healthy immune system," said Donald Kohn, the study's principal investigator at UCLA (USA).

But if gene therapy achieves such promising results, why are there so few studies with the therapy worldwide?

“There are more than 150 gene therapy clinical trials underway, but only a handful of approved therapies,” says Claire Booth, an expert in gene therapy and pediatric immunology at University College London .

However, "in the last two years, commercial manufacturers have abandoned six gene therapies for non-medical reasons," adds Booth, who is also a physician at Great Ormond Street Hospital in London and one of the researchers on the study published in New England. "To achieve sustainable and affordable access to life-changing gene therapies for rare inherited diseases, an evolution is needed."

The problem with gene therapy is that it has developed much more slowly than we would like, says Julián Sevilla. "At the beginning of the century, it received very bad press: in the 1990s, some clinical trials caused cases of leukemia, which halted all research. Since then, it has improved a lot. We used to say that something like this had never been done, but with COVID, we saw that when there is money and interest, progress is made quickly."

Once these initial problems are overcome, replacing retroviral vectors with much safer lentiviral vectors is revolutionary. "We can modify blood cells to reverse a genetic disease, which is much less aggressive than a transplant."

Gene therapy has been recognized again thanks to CAR-T cell therapy, which has brought about a change in the treatment of some cancers such as leukemia and lymphoma. However, Sevilla explains, CAR-T cells are still the younger brother of gene therapy because they are a modification of lymphocytes. They have served to demonstrate that genetic manipulation of cells is not science fiction and that they achieve very good results.

Booth points out that developing a gene therapy costs $5 billion (€4.6 billion), five times more than marketing a traditional drug.

"Manufacturing an advanced therapy drug is expensive," Sevilla says. "For example, in hemophilia, some treatments cost two million euros. When you compare that to a transplant, it seems exorbitant, but the truth is we don't have clear studies on how much a transplant actually costs, including hospitalizations and complications."

However, he acknowledges, one of the arguments put forward against it is that we cannot guarantee 100% that the patient will be "cured" for life. "Although we have patients with more than 20 years of follow-up who are doing well, they are required to demonstrate stability at 15 years, something that was never required, for example, with bone marrow transplants."

The potential of gene therapy is especially important now in rare diseases, where there are no other options.

Sevilla points out that initially, clinical trials, like the one published in New England, were conducted in patients without a compatible donor. "But once you demonstrate that it's effective, it should be competitive even with transplantation. The problem is that regulatory agencies require randomized trials comparing gene therapy and transplantation, when transplantation has never been subjected to that type of comparison."

Sevilla points out that there are already some studies, such as those by Dr. Kohn at UCLA, that have shown improved long-term survival rates with gene therapy for immunodeficiencies, but because they are small series, they fail to generate sufficient impact.

Furthermore, he adds, since these are rare diseases, the patient groups are very small and have little lobbying capacity.

That's why the Agora initiative was born in Europe, led by Dr. Booth, which seeks to recover patents abandoned by companies so that treatments can continue to be developed in academia.

AGORA was founded in September 2022 by around 50 academics, physicians, and patient organizations concerned about the pharmaceutical industry's divestment from gene therapy.

Developing a gene therapy is a long process.

Sevilla explains that in the case of severe leukocyte adhesion deficiency I or LAD-I, a clinical trial was initiated and completed in nine years, "but with Fanconi anemia it took us twenty. In other diseases, such as pyruvate kinase deficiency, we've been on the trial for 15 years and have four patients treated with excellent results, but we're blocked because the company hasn't opened Phase II. Sometimes it's not a scientific problem, but a business strategy problem ."

Although transformative results from some gene therapies have already been observed in our patients, Booth comments, some of these therapies were either removed from companies' programs or the necessary licenses were not obtained.

Although these therapies have proven highly effective in clinical trials, they are not truly commercially viable. The patient population receiving these therapies for rare and ultra-rare diseases is very small; in some cases, perhaps 20 patients per year worldwide, the British researcher acknowledges, says Both.

Although there are few cases of patients who have benefited from gene therapy, Sevilla is clear that gene therapy is curative. " I dare say our patient is cured ."