Gene Therapy Shows Long-Term Benefit for Patients with a Rare Pediatric Brain Disease

Clinical trial of 32 patients with cerebral adrenoleukodystrophy found that after six years most remained free of major disabilities

Cerebral adrenoleukodystrophy (CALD) is a rare progressive, genetic brain disease that primarily presents in young boys, causing loss of neurological function and ultimately leading to early death. Researchers from Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, Boston Children’s Hospital, and collaborators 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. Findings, published in two articles in the New England Journal of Medicine, describe long-term outcomes in those treated with the eli-cel gene therapy, while also highlighting safety concerns about the emergence of blood cancers post-treatment.

“Cerebral adrenoleukodystrophy is a devastating brain disease that strikes children in the prime of their childhood and development,” said Florian Eichler, MD, director of the Leukodystrophy Clinic in the Department of Neurology at Massachusetts General Hospital, first author of the paper on long-term outcomes. “When I initially began treating patients with CALD, 80 percent came into our clinic on death’s door, and now the ratio has flipped. We cautiously celebrate that we have been able to stabilize 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 U.S. Food and Drug Administration approved the first gene therapy for CALD, elivaldogene autotemcel (eli-cel), which was clinically evaluated by the researchers from Mass General and Boston Children’s Hospital. In the new study, 32 boys aged 3 to 13 years with early-stage CALD received eli-cel as part of the ALD-102 trial, which was sponsored by bluebird bio, Inc., the company that developed the therapy.

The therapy uses a Lenti-D lentiviral vector to add 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 hematologic malignancy that appears to have been triggered by the Lenti-D lentiviral 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 hematologic malignancy (MDS in five patients and acute myeloid leukemia in one) which appear to be also caused by the vector. These results were reported in a second paper published in the same volume of the journal. 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 leukemia in this second trial.

“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,” said Christine Duncan, MD, medical director of Clinical Research and Clinical Development in the Gene Therapy Program at Boston Children’s Hospital and first author of the second report. “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 hematologic malignancy, which are complex and not yet fully elucidated. Improving lentiviral vectors and refining HSCT regimens for CALD are a high priority. 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, especially those lacking matched donors for allogeneic HSCT.

"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," said David A. Williams, MD, chief of the Division of Hematology/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."

Disclosures: Dr. Christine Duncan and Dr. David A. Williams are consultants for bluebird bio. Additional disclosures can be found on NEJM.org.

Funding: Funding provided by bluebird bio.

Papers cited: Eichler F, et al. “Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy” New England Journal of Medicine DOI: 10.1056/NEJMoa2400442

Duncan CN, et al. “Hematologic Malignancy After Gene Therapy for Cerebral Adrenoleukodystrophy” New England Journal of Medicine DOI: 10.1056/NEJMoa2405541