Gene therapy shows long-term benefits for patients with rare pediatric brain disease

Cerebral adrenoleukodystrophy (CALD) is a rare and progressive genetic brain disease that occurs primarily in young boys, causing loss of neurological function and ultimately leading to premature death.

Researchers from Massachusetts General Hospital, Boston Children’s Hospital and colleagues showed that six years after treatment with the first approved gene therapy for CALD, 94% of patients showed no decline in neurological functioning, and more 80% of them do not suffer from a major disability.

Results, published in two articles in the New England Journal of Medicinedescribe long-term outcomes in people treated with eli-cel gene therapy, while highlighting safety concerns regarding the emergence of blood cancers after treatment.

“Cerebral adrenoleukodystrophy is a devastating brain disease that strikes children in the prime of 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 article on long-term illnesses. long-term results.

“When I started treating CALD patients, 80% of them entered our clinic at death’s door, and now the ratio has reversed. We cautiously celebrate the fact that we were able to stabilize this neurological disease and return these boys to fulfilling lives, but this jubilation is dampened by the fact that we are seeing malignancy in a subset of these patients. This is something we are actively trying to understand and resolve.

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 researchers at Mass General and Boston Children’s Hospital.

In the new study, 32 boys ages 3 to 13 with early-stage CALD received eli-cel as part of the ALD-102 trial, sponsored by bluebird bio, Inc., the company that developed the therapy.

The therapy uses a lentiviral vector Lenti-D to add a healthy copy of the ABCD1 gene, defective in people with CALD, to blood stem cells that have been taken from the patient. These stem cells are then reintroduced to the patient via autologous hematopoietic stem cell transplantation (HSCT). Using a patient’s own cells significantly reduces the risk of graft-versus-host disease, a risk posed by other forms of treatment.

In the ALD-102 trial, a patient developed a condition known as myelodysplastic syndrome (MDS) with excess blasts, a hematologic malignancy that appears to have been triggered by the lentiviral vector Lenti-D used to deliver the therapy. genic.

In a second, more recent trial of eli-cel therapy (ALD-104), six out of 35 patients developed a hematologic malignancy (MDS in five patients and acute myeloid leukemia in one), which also appears to be caused by the vector. These results were reported in a second article published in the same volume of the journal.

The protocol of the second trial, ALD-104, differed from the first in using a different chemotherapy drug during HSCT (fludarabine instead of cytoxan) and other changes that may have contributed to the apparent increased risk of leukemia in this second trial.

“Our leukemia paper in this disease is a key step in assessing the risks associated with e-cell therapy and lentiviral vector technology,” said Christine Duncan, MD, medical director of clinical research and clinical development. of the Gene Therapy Program at Boston Children’s Hospital and first author of the second report.

“While the overall trial results are optimistic, we hope to expand our research to inform future follow-up to provide families facing a devastating illness with more information and options.”

Researchers will continue to study potential causes of hematologic malignancy, which are complex and not yet fully understood. Improving lentiviral vectors and perfecting HSCT regimens for CALD are a high priority.

As newborn screening for adrenoleukodystrophy improves opportunities for early detection of CALD, opportunities to identify patients who may benefit from gene therapy could be expanded, particularly those who lack matched donors for allogeneic HSCT.

“As a clinician and principal investigator, it is truly inspiring to witness the significant progress we have made over the past decade in the fight against CALD,” said David A. Williams, MD, chief of the Division of Hematology/Oncology in Boston. Children’s Hospital.

“While the risks associated with gene therapy and vector technology are real, the progress we have made offers hope to families facing limited options. Every progress brings us closer to the answers these families desperately need.

“Our commitment to refining and improving the safety of the vector through continued research remains unwavering, as we work tirelessly to ensure the long-term safety and effectiveness of gene therapy treatments for this devastating disease. These efforts involve several researchers from around the world and are ongoing. “