Gene therapy for ADA-SCID: positive long-term results, now at work to ensure early diagnosis and access

In Nature Medicine, a study by the San Raffaele-Telethon Institute in Milan reports the data of 43 patients treated with one of the first advanced therapies approved in the world, result of Italian research.

Gene therapy for the rare immunodeficiency ADA-SCID is confirmed to have a favorable risk to benefit ratio also in the long term: this is what emerges from a study published in Nature Medicine by physician scientists and researchers from the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) of Milan. The study presents the data of 43 patients treated since 2000, 19 of which after the registration of the therapy in the European Union in 2016 . That for ADA-SCID is in fact one of the most “long-lived” advanced therapies as it was among the first in the world to be approved as drug. From 2023 , Fondazione Telethon is responsible for the production and distribution of this therapy, thus avoiding its withdrawal from the market after the disinvestment by the manufacturing company given the poor economic return.

ADA-SCID is a very rare genetic disease: the annual incidence is estimated between 1/375,000 and 1/660,000 live births . Based on data of new births in the European Union (around 4 million per year ), it is estimated that between 6 and 11 children are born with this pathology every year in the 27 EU countries. ADA-SCID is due to the defect in the adenosine deaminase gene, an enzyme essential for the production and maturation of lymphocytes, a particular type of white blood cell. Without this protein, the immune system does not develop properly and is unable to fight even the most common infections, which can be fatal. These children are therefore forced to live in a sterile and isolated environment, so much so that the expression "bubble children" has been coined for them.

Currently the first therapy of choice for ADA-SCID is the transplant of blood stem cells from a compatible family donor, which can cure the disease but is available in less than 20% of cases . When this is not feasible, gene therapy represents a valid alternative therapeutic option: it is administered only once in a lifetime and consists of a vector of viral origin containing a corrected version of the defective gene in patients. When put into contact with blood stem cells taken from the patient himself, the vector allows the restoration of the production of the missing protein. Once reinfused into the blood, the corrected cells give life to functioning lymphocytes and thus defend the body from infections.

"In this work we describe how after marketing, gene therapy for ADA-SCID continues to be safe and effective, as already demonstrated in the experimental clinical phase begun in 2000? comments Maddalena Migliavacca, pediatric immunologist and researcher in the Pediatric Immunohematology Unit. ?The patients are all alive and in most cases they did not require further curative therapies after gene therapy. Their quality of life improved significantly, they were able to undergo regular vaccinations, go to school and finally lead a community life. In the few cases - around 15% - in which the treatment did not work, we were able to successfully intervene with a donor-derived transplant. We will continue to follow our patients for at least 15 years after the administration of the therapy to monitor long-term safety: this will allow us to study even little-known aspects of this disease not linked to immunity, such as neurological and metabolic ones."

The long-term observation of these patients has once again highlighted the importance of early diagnosis. As Maria Pia Cicalese, pediatric immunologist and researcher at the Vita-Salute San Raffaele University, explains:

"The sooner we are able to intervene, the better the response to treatment, because the period of time in which the disease can damage the organism is reduced. Thanks to the experience gained in recent years, we have improved our approach, patients are able to undergo gene therapy treatment in better conditions and this also has an impact on long-term efficacy. This is why it is essential that newborn screening for ADA-SCID is spread as widely as possible: this test allows the disease to be identified at birth and therefore to intervene before it has caused irreparable damage. Unfortunately, however, we are still far from applying this type of test to the entire population."

At present in Italy neither ADA-SCID nor other severe combined immunodeficiencies are part of the national neonatal screening panel. Some regions, however, have activated pilot projects: the first was Tuscany, back in 2011. In recent years, as reported by the Osservatorio Malattie Rare , Campania and Liguria have conducted screening programs for research purposes, as well as the University Hospital of Padua and the screening center of Palermo. The latest regions to have introduced screening were Abruzzo, Puglia and Lombardy. In the world, however, among the countries that have introduced screening for this pathology are Germany, the United Kingdom, the Netherlands, Sweden, Ireland, Israel, Brazil, India and the United States.

The study also highlighted the disparities in access to therapy: the drug is administered only in Italy at the Ospedale San Raffaele, the only authorized centre. For Italian patients, reimbursement by the national healthcare system is automatic, while for those from other European Union countries it takes place only following authorization by the healthcare system of the country of origin.

"Unfortunately, this step is not always easy – comments Alessandro Aiuti, Deputy Director of SR-Tiget and full professor of Pediatrics at the Vita-Salute San Raffaele University of Milan. ?Among the patients eligible for gene therapy who were referred to us, some did not receive the treatment due to difficulties in accessing the reimbursed therapy. Fondazione Telethon has made a great effort in recent years to facilitate access thanks to the "Come a casa " program, which offers 360-degree support to families who come to Italy for treatment - but it is not enough. There is no doubt that the cost of the therapy is high when compared to traditional drugs; however, the economic impact is reduced if we consider that the therapy is administered only once in a lifetime, especially if we compare it with chronic therapies administered throughout life. In the case of therapies that can change the natural history of such serious diseases like ADA-SCID, it is essential to guarantee access to treatment to all patients who need them, however rare they are."

?? Read the full research paper published on Nature Medicine here https://www.nature.com/articles/s41591-023-02789-4

This article is a translation of the press release originally published in italian by Fondazione Telethon.