Cerebral adrenoleukodystrophy (CALD) is a rare genetic brain disease that primarily affects young boys, leading to a loss of neurological function and early death. Researchers from Massachusetts General Hospital and Boston Children’s Hospital have shown that six years after treatment with the first gene therapy approved for CALD, 94 percent of patients have had no decline in neurological functioning, with over 80 percent remaining free of major disability. The findings, published in two articles in the New England Journal of Medicine, highlight the long-term outcomes of those treated with the elivaldogene autotemcel (eli-cel) gene therapy, while also raising safety concerns about the emergence of blood cancers post-treatment.
Dr. Florian Eichler, director of the Leukodystrophy Clinic at Massachusetts General Hospital, expressed cautious celebration over the ability to stabilize the neurologic disease and provide these boys with a fulfilling life, despite the emergence of malignancy in a subset of patients post-treatment. The U.S. Food and Drug Administration approved the eli-cel gene therapy in 2022, and the therapy involves adding a healthy copy of the faulty ABCD1 gene to blood stem cells, which are reintroduced to the patient through an autologous hematopoietic stem cell transplantation (HSCT). This personalized approach significantly reduces the risk of graft-versus-host disease seen in other treatments.
In the ALD-102 trial, 32 boys with early-stage CALD received eli-cel, with one patient developing myelodysplastic syndrome (MDS) post-treatment, possibly triggered by the Lenti-D lentiviral vector used in the therapy. A second trial, ALD-104, reported six cases of hematologic malignancy (MDS in five patients and acute myeloid leukemia in one) associated with the lentiviral vector. The researchers are keen on evaluating the risks associated with the therapy and vector technology to inform future follow-up and provide families facing CALD with more information and treatment options.
Dr. Christine Duncan, medical director of Clinical Research and Clinical Development in the Gene Therapy Program at Boston Children’s Hospital, emphasized the need to improve lentiviral vectors and refine HSCT regimens for CALD, as well as the importance of newborn screening for early detection of the disease. While the risks of gene therapy and vector technology are real, the progress made in the fight against CALD offers hope for families facing limited treatment options. Dr. David A. Williams, chief of the Division of Hematology/Oncology at Boston Children’s Hospital, highlighted the ongoing commitment to research in order to ensure the long-term safety and efficacy of gene therapy treatments for CALD, with efforts involving multiple investigators worldwide.