Cerebral adrenoleukodystrophy (CALD) is a fatal disease of children and young men with progressive neurological deficit and life expectancy of within several years of onset of symptoms. Another experimental treatment in collaboration with our colleagues from Massachusetts General Hospital and Boston Children’s Hospital demonstrated that more than six years since the first time gene therapy was administered for CALD, 94% of the patients have not shown any deterioration of the neurological deficits; over 80 patients are considered to be free of major disability.
But the people, as reported in two studies published in the New England Journal of Medicine, say identifying long-term survival after eli-cel gene therapy is possible, as is consideration of issues about blood cancers after celgene therapy.
Cerebral adrenoleukodystrophy is a fatal cerebral demyelinating disease that affects children in the most productive period of their childhood and brain development, noted the first author of the paper on long-term outcomes, Dr. Florian Eichler, MD, director of the Leukodystrophy Clinic in the Department of Neurology at Massachusetts General Hospital.
When I first started working with patients with CALD, 80% of them were virtually moribund when they arrived at our clinic and today, that ratio is reversed. We have reason to cautiously rejoice that we are able to stabilize this neurologic disease and award these boys a fulfilling life again, but that rejoicing is clouded by the knowledge that we witness malignancy in a number of these patients.
This is something that we are actively trying to understand and reduce. In 2022, the U.S. Food and Drug Administration approved the first gene therapy for CALD and was clinically developed by the research team of Mass General and Boston Children Hospital known as elivaldogene autotemcel or (eli-cel).
In a new trial, 32 males diagnosed with CALD at age under 4 with early-phase disease who were aged between 3 and 13 years received eli-cel transplanted from the ALD-102 trial sponsored by bluebird bio., Inc., the developer of the therapy. The therapy involves a Lenti-D lentiviral vector to insert a correct copy of the ABCD1 gene which is impaired in those with CALD into the blood stem cells that are taken from the patient.
These stem cells are then returned to the patient by an autologous hematopoietic stem cell transplantation (HSCT). When a patient’s own cells are used there is significantly a reduced risk ofvecsus host disease, a hazard of other forms of therapy. In the ALD-102 a patient developed a hematologic malignancy known as myelodysplastic syndrome (MDS) with excess blasts and seems to have developed from the Lenti-D lentiviral vector that was employed in the delivery of the gene therapy.
In the second and presumably more recent trial of the eli-cel (ALD-104), 35 patients had a hematologic malignancy in 6 cases, MDS in 5 and acute myeloid leukemia in one, that is also linked with the vector. These latter results are described in the second paper also published in the same volume of the same journal.
The actual strain of treatment for the second trial, ALD-104 was slightly different from the first in that during the HSCT Phase, the chemotherapy used was fludarabine instead of cytoxan and other factors that might have led to what seems like a heightened likelihood of leukemia in this second trial.
Our paper on leukemias in this condition is used as an initial step to assess the dangers of… eli-cell therapy and lentiviral vector technology’, said Christine Duncan, MD; medical director of Clinical research and clinical development for the Gene therapy programme, at Boston Children’s hospital and the first author of the second report. The overall trial results are positive but we would like to carry out further study to give families where a devastating disease exists more information and choices in the future follow ups.’
The researchers will go on investigating the prospective causes of hematologic malignancy, which are still unsolved and multifaceted.
Optimizing the lentiviral vectors and further calcification of HSCT for CALD are considered a priority. Given the recent advances in newborn screening for ALD, meaning that early diagnosis of CALD may become more frequent, there might be a chance to find more patients, who could benefit from gene therapy in cases of absence of anMN matched donor allogeneic HSCT.
‘It is pleasing to see that over the last decade there have been great advances in addressing CALD as both an academic clinician and a senior investigator,’ Dr David A Williams, chief Division of Hematology/ Oncology, Boston Children Hospital, USA. Despite the dangers posed by gene therapy and vector technology are real, the developments made toward finding a cure give hope to those families that are left with not many choices. Each development takes the scientific community closer to the answers these families so badly seek.
Reference: Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy, New England Journal of Medicine (2024).
