On December 4, 2010, Nice Premium visited the biotherapy department at Necker Hospital in Paris. Supported by the AFM, thanks to donations from the Telethon, it is at the heart of recent global successes in gene therapy for rare diseases. Marina Cavazzana-Calvo, who leads this structure, and Salima Hacein-Bey-Abina, head of the gene therapy laboratory, explain what gene therapy is.
The biotherapy department, under the direction of Marina Cavazzana-Calvo, represents a major advancement in the development of innovative therapies. Inaugurated in 2007, it was made possible by donations from the Telethon. Its goal? To foster biotherapies. These include therapeutic methods based on the use and manipulation of living cells in a laboratory. Of Greek origin, the term bio means life, and therapy corresponds to treatment. Marina Cavazzana-Calvo explains the department’s expertise: “Our know-how is based on the grafting of compatible or partially compatible hematopoietic stem cells and on the gene therapy of hematopoietic stem cells.” Manufactured by the bone marrow, they are the origin of the various blood cells (red blood cells, white blood cells, and platelets). They can be genetically modified in the laboratory.
Three essential therapeutic strategies are developed and managed in this department: gene therapy, which involves replacing the function of a deficient or missing gene with that of a therapeutic gene inserted into the cell. Cellular therapy aims to graft healthy cells where others are dead or defective. Plasma exchanges are also part of the innovative strategies developed. They allow the collection of plasma (the liquid component in blood) from a blood donor or a patient. This technique is necessary for treating acute and chronic rejections in organ transplant patients. In this 550 m² laboratory, researchers develop protocols from start to finish: from pre-clinical trials (conducted on animals or cell cultures) to clinical trials, during which the tolerance and efficacy of a treatment are tested. Marina Cavazzana-Calvo collaborates notably with Salima Hacein-Bey-Abina, head of the gene therapy laboratory. Both have developed gene therapy protocols. “Salima and I have developed nearly all the gene therapy protocols over the past fifteen years, especially the one for bubble babies.” In reality, these children suffer from severe combined immunodeficiency linked to the X chromosome.
By the end of the year, the new protocol for the Wiscott-Aldrich syndrome will be implemented. This immune deficiency is characterized by a significant decrease in the blood platelet count. It is important to mention that the development of a clinical trial spans several years. Salima Hacein-Bey-Abina emphasizes: “These are tailor-made developments. Innovative therapies and biotherapies are defined as tailor-made therapies, pending their generalization. It’s somewhat the objective and interest of this development. It serves as proof of concept before moving on to more common, frequent pathologies.”
Gene Therapy: For Whom?
Emerging in the 1990s, it was initially proposed to adult patients. Marina Cavazzana-Calvo explains the reason: “We agreed that it was ethically better to offer gene therapy to adult patients who are capable of giving their own consent given the known risks of gene therapy. And then to extend it to a pediatric population once we have fully understood the potentially unpredictable risks associated with gene therapy.” American scientists have shown that gene therapy can cause the development of leukemic tumors. Patients with immune deficiency treated with gene therapy developed leukemia. In 2000, the team of Professor Alain Fisher and Marina Cavazzana-Calvo at Necker Hospital announced the success of gene therapy on “bubble babies.” 11 children condemned to live in a sterile environment to avoid contact with germs received a gene therapy treatment. Two of them contracted a form of leukemia due to an insertion error of the therapeutic gene, according to a study published in “Science” in October 2003. It’s important to note that gene therapy is proposed for patients meeting certain criteria: “In general, they are not too advanced in the disease, but their quality of life is still compromised due to the disease,” explains Marina Cavazzana-Calvo.
This therapeutic treatment is akin to a transplant. It requires hospitalization of the patient for one to three months, depending on the type of pathology. Marina Cavazzana-Calvo explains the procedure of gene therapy treatment: “In the simplest cases, it involves a month of hospitalization. But manipulating the cells takes a few days. Once handled, they are frozen in the case of beta-thalassemia (a blood disease). We then conduct a series of exams to ensure what we have done.” After necessary checks (control over the manipulated cells), the patient is contacted and offered hospitalization. “In fact, the patient receives an injection, the graft. Then, it’s necessary to prove that this cell injection is effective. It lasts about a month, a certain time. In the meantime, the patient will receive other therapies. But the specific treatment of genetically modified cells is done only once,” adds Salima Hacein-Bey-Abina.
An Uncertainty
The word uncertainty is linked to gene therapy. “We don’t know how long it will work. We are in an uncertainty that pushes us to be cautious,” confides Marina Cavazzana-Calvo. Two patients with beta-thalassemia (a blood disease) were treated with gene therapy. For one of them, it was a failure. Why? The number of genetically modified cells reinjected was insufficient. No aggravation, nor benefit, of his disease was discovered. The second patient received a sufficient number of genetically corrected cells. Gradually, his need for blood transfusions diminished. “We were able to stop them about a year after gene therapy,” explains Marina Cavazzana-Calvo.
Doubts still linger about gene therapy, but positive results prove there is reason to believe in it: “Today, from the trials we’ve conducted at Necker, we have beneficial results that allow us to continue proposing these protocols in the years to come, and even to expand them. We don’t have any disillusionment with gene therapy that prevents us from developing this strategy further.” However, in some diseases, gene treatment did not produce any results. This is the case with in vivo gene therapy for certain pathologies. The therapeutic gene is directly injected intravenously or locally to reach target cells. This gene therapy implies broader constraints, especially concerning the type of vector. “To date, the trials yielding the best results are ex vivo gene therapy trials,” states Salima Hacein-Bey-Abina. This technique involves collecting bone marrow or blood cells from the patient. They are then transformed in the laboratory and reinjected into the patient. However, some types of in vivo gene therapy are working effectively today, particularly in the brain.
Today, a dozen pathologies benefit from gene therapy. Funding a clinical trial is a “headache,” confesses Marina Cavazzana-Calvo. It costs millions of euros. The AFM, Public Assistance, and the Medical Research Foundation constitute valuable financial aids. This weekend, on the occasion of
the 24th Telethon, you can support the AFM and thus contribute to the development of therapeutic trials.
