Gene therapy has emerged as one of the greatest hopes for the treatment of rare diseases, including cerebral adrenoleukodystrophy (CALD). This progressive and devastating genetic disease primarily affects young children, causing a rapid loss of neurological function, which can lead to severe disability and, in many cases, premature death. Without effective treatments until a few years ago, CALD represents a major medical challenge and a source of suffering for affected families.
A team of researchers from Massachusetts General Hospital and the Boston Children’s Hospital has made significant progress in the treatment of CALD thanks to the first gene therapy approved for this disease, known as elivaldogene autotemcel (eli-cel). Six years after receiving this treatment, 94% of patients have shown no deterioration in their neurological functioning, and more than 80% remain free of significant disabilities, which represents a notable change in the evolution of the disease. The findings have been published in two articles in the ‘New England Journal of Medicine‘.
Eli-cel gene therapy uses a lentiviral vector, Lenti-D, to introduce a functional copy of the defective ABCD1 gene, responsible for the disease, into blood stem cells taken from the patient themselves. These modified stem cells are reintroduced into the body through an autologous hematopoietic stem cell transplant. (HSCT). This approach greatly reduces the risk of graft-versus-host disease, a common complication in traditional allogeneic transplants.
Despite these encouraging results, concerns have been raised about the safety of the therapy, as some patients have developed hematologic malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia. In the first clinical trial, ALD-102, one patient developed MDS, while in a second trial, ALD-104, six of 35 treated patients developed hematologic malignancies, suggesting that the Lenti-D vector could be linked to these cases.
The second clinical trial used a slightly different protocol, using a chemotherapy (fludarabine) during transplantation instead of cytoxan, which could have influenced the increased risks of leukemia observed. This has led researchers to further investigate the underlying causes of these blood cancers, with the goal of improving lentiviral vectors and transplant regimens to minimize these serious side effects.
Despite these risks, researchers highlight the positive impact of the therapy. According to Florian Eichlerlead author of the study, a few years ago most children with CALD arrived at his clinic in a terminal state, while today many can live full lives without serious disabilities. However, the team emphasizes the need for caution and to continue investigating oncological complications in order to offer greater safety to patients.
eli-cel gene therapy was approved by the US Food and Drug Administration. in 2022, and its development was led by biotechnology company bluebird bio, Inc. In the ALD-102 clinical trial, 32 children ages 3 to 13 with early-stage CALD received the treatment. The success of the therapy lies in its ability to stop the progression of the disease in the majority of cases, which represents hope for families affected by this devastating condition.
The progress made in the last decade is inspiring and offers a source of hope for families facing limited options
Early detection of adrenoleukodystrophy in newborns has been identified as a crucial tool to improve treatment outcomes. By identifying the disease in its early stages, it is possible to intervene before neurological damage is irreversible, opening new opportunities for the use of gene therapy, especially in patients who do not have compatible donors for an allogeneic stem cell transplant. .
David A. Williams, one of the lead researchers, said the progress made over the past decade is inspiring and offers a source of hope for families facing limited options. Although the risks associated with gene therapy and the use of lentiviral vectors are real, each scientific advance brings doctors and scientists closer to the answers that families affected by CALD desperately need.
In summary, gene therapy for cerebral adrenoleukodystrophy has proven to be a revolutionary intervention that has transformed the prognosis of many affected children. However, significant challenges remain in terms of safety, underscoring the need to continue researching and improving available therapies to ensure their long-term efficacy and safety. Researchers are committed to improving lentiviral vectors and refining treatments to maximize benefits and minimize risks, with the ultimate goal of providing a safe and effective cure for this devastating disease.
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