2024-10-10 11:18:00
Gene therapy has emerged as one of the greatest hopes for treating rare diseases, too cerebral adrenoleukodystrophy (HEAT). This progressive and devastating genetic disease primarily affects young children, causing 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 serious 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 with the first gene therapy approved for this disease, known as elivaldogene autotemcel (eli-cel). Six years after receiving this treatment, 94% of patients showed no deterioration in their neurological functioning and more than 80% had no significant disability, which represents a notable change in the evolution of the disease. The findings were published in two articles in ‘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 patients 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 hematological 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 patients treated developed hematologic malignancies, suggesting that the Lenti-D carrier may be linked to these cases.
The second clinical study used a slightly different protocol, using a chemotherapy (fludarabine) during transplantation instead of cytoxane, which may have influenced the observed increased risk of leukemia. 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. Second Florian Eichlerlead author of the study, a few years ago most children with CALD arrived at his clinic in a terminal state, whereas today many can live full lives without serious disabilities. However, the team emphasizes the need for caution and to continue investigating oncological complications to provide greater safety for patients.
Eli-cel gene therapy was approved by 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 aged 3 to 13 years with early-stage CALD received the treatment. The success of the therapy lies in its ability to halt the progression of the disease in the majority of cases, which represents hope for families affected by this devastating disease.
The progress made over the past decade is inspiring and offers a source of hope for families facing limited options
Early diagnosis of adrenoleukodystrophy in newborns has been identified as a crucial tool for improving treatment outcomes. By identifying the disease in its early stages, it is possible to intervene before the neurological damage is irreversible, opening up 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. While the risks associated with gene therapy and the use of lentiviral vectors are real, every 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 safety challenges remain, underscoring the need for continued research and improvement of 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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