Report gives update on boys with rare brain disease 6 years after gene therapy

Most boys treated with breakthrough gene therapy for a rare but deadly brain illness are faring well six years later, two new reports find.

The 77 boys were treated for cerebral adrenoleukodystrophy (CALD), a formerly incurable and progressive genetic brain disease that typically led to a loss of neurological function and early death.

However, most patients treated with "eli-cel" gene therapy six years ago are still showing no declines in brain function and remain free of disability, researchers reported Wednesday in two studies published in the New England Journal of Medicine.

There was a disturbing finding from one of the two studies, however: Six of 35 patients who received one form of the gene therapy have developed blood cancers that seemed tied to the gene therapy.

However, the overall news is positive for children who otherwise faced a death sentence, the researchers said.

"Cerebral adrenoleukodystrophy is a devastating brain disease that strikes children in the prime of their childhood and development," explained Dr. Florian Eichler , director of the Leukodystrophy Clinic in the Department of Neurology at Massachusetts General Hospital and lead author of one of the two studies. "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," Eichler said in a hospital news release.

However, "that jubilation is dampened by the fact that we see malignancy in a subset of these patients," he said. "This is something that we are actively trying to understand and address."

Eli-cel stands for elivaldogene autotemcel. It's a form of gene therapy that places a healthy form of the ABCD1 gene onto a viral vector, called Lenti-D lentivirus.

A malfunctioning form of the ABCD1 is the root cause of CALD, the researchers explained.

In the lab, eli-cel gene therapy is added to blood stem cells derived from the patient. These are then re-infused back into that patient, ready to correct the genetic error.

In one study tracking the six-year follow-up of 32 boys who underwent eli-cel gene therapy between the ages of 3 and 13, 94% have shown no sign of neurological decline and 80% are free of disability.

However, in a second trial of 35 boys treated with eli-cel for CALD, researchers say six developed a blood malignancy that doctors attribute to the viral vector used in the gene therapy.

Five of the boys have what's known as a myelodysplastic syndrome (MDS), which the Mayo Clinic describes as a disease of bone marrow cells "caused by blood cells that are poorly formed or don't work properly." People with MDS often require blood transfusions, medications or even stem cell transplants to boost their blood cell production.

One other boy developed acute myeloid leukemia (AML), where white blood cells are overproduced.

Why did some boys in the second trial develop blood cancers, while those in the first trial did not?

According to the Boston team, the answer could lie in differences in the type of chemotherapy drug that was used as part of the stem cell transplants the patients received. They speculate that the use of fludarabine instead of cytoxan, as well as other changes in protocol, could have upped the patients' risk for cancer.

It's a sobering reminder that gene therapies do not come without risks, the experts said.

"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 Dr. Christine Duncan , 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."

Duncan and her colleagues are working hard to pinpoint the cause of the rise in cancer risk, and how to prevent it in future eli-cel gene therapy procedures.

Overall, the news is good, stressed Dr. David Williams , chief of the Division of Hematology/Oncology at Boston Children's Hospital.

"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," Williams said.

"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," he added. "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."

The studies were finded by bluebird, bio, Inc., which developed the new gene therapy.

More information

Find out more about cerebral adrenoleukodystrophy at the ALD Alliance .

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