Gene therapy has emerged as a potential long-term treatment for CALD, a devastating, rare brain disease which causes loss of neurological function and ultimately an early death in children.
CALD (cerebral adrenoleukodystrophy) is a progressive, genetic brain disease that primarily presents in young boys.
Researchers have found that six years after treatment with the first gene therapy approved for CALD, 94 per cent of patients had no decline in neurological functioning, with over 80 per cent remaining free of major disability.
First author of the long-term study into the treatment, Florian Eichler of the neurology department at Massachusetts General Hospital, says: “[CALD] is a devastating brain disease that strikes children in the prime of their childhood and development.
“When I initially began treating patients with CALD, 80 per cent came into our clinic on death’s door, and now the ratio has flipped. We cautiously celebrate that we have been able to stabilise this neurologic disease and give these boys back a fulfilling life, but that jubilation is dampened by the fact that we see malignancy in a subset of these patients. This is something that we are actively trying to understand and address.”
In 2022, the US Food and Drug Administration approved the first gene therapy for CALD, elivaldogene autotemcel (eli-cel), which was clinically evaluated by the researchers from Massachusetts General Hospital and Boston Children’s Hospital.
In the new study, 32 boys aged three to 13 years with early-stage CALD received eli-cel as part of the ALD-102 trial.
The therapy adds a healthy copy of the ABCD1 gene, which is faulty in those with CALD, to blood stem cells that have been removed from the patient.
These stem cells are then reintroduced to the patient via an autologous hematopoietic stem cell transplantation (HSCT). Using a patient’s own cells substantially reduces the risk of ‘graft-versus host disease’ – a risk posed by other forms of treatment.
In the ALD-102 trial, one patient developed a condition known as myelodysplastic syndrome (MDS) with excess blasts, a haematologic malignancy that appears to have been triggered by the vector used to deliver the gene therapy.
In a second, more recent trial of the eli-cel therapy (ALD-104), six of 35 patients have developed a haematologic malignancy (MDS in five patients and acute myeloid leukemia in one) which appear to be also caused by the vector.
The protocol for the second trial, ALD-104, differed from the first in that it uses a different chemotherapy drug during HSCT (fludarabine instead of cytoxan) and other changes that may have contributed to the apparent increase risk of leukaemia in this second trial.
Christine Duncan, medical director of clinical research and clinical development in the gene therapy programme at Boston Children’s Hospital, says: “Our paper on leukemias in this condition serves as a key step to evaluate the risks associated with the eli-cell therapy and lentiviral vector technology.
“Although the overall trial results are optimistic, we hope to expand our research to inform future follow-up to provide families facing a devastating disease with more information and options.”
The researchers will continue to study the potential causes of haematologic malignancy, which are complex and not yet fully elucidated.
With newborn screening for adrenoleukodystrophy improving the possibility of early detection of CALD, there may be expanded opportunities to identify patients who may benefit from gene therapy, researchers say.
“As both a clinician and senior investigator, it’s truly inspiring to witness the significant strides we’ve made over the past decade in the fight against CALD,” says David Williams, chief of the division of heamatology/oncology at Boston Children’s Hospital.
“While the risks associated with gene therapy and vector technology are real, the progress we’ve made offers a source of hope for families facing limited options.
“Every advancement brings us closer to the answers these families desperately need. Our commitment to refining and improving the vector’s safety by continued research remains unwavering, as we work tirelessly to ensure the long-term safety and efficacy of gene therapy treatments for this devasting disease. These efforts include multiple investigators world-wide and are underway.”
