FDA Halted Phase 3 Trial for Cerebral Adrenoleukodystrophy Due to Participant Developing MDS


 Science Magazine recently joined other news sources in reporting that Bluebird Bio’s Phase 3 clinical trial investigating a treatment for a neurological disease was put on hold by the FDA. The hold was due to a participant developing a bone marrow disease that is a precursor to leukemia.

Cerebral adrenoleukodystrophy is a genetic disorder causing damage to the myelin sheath (membrane) that insulates nerve fibers in the spinal cord and brain.

Cerebral adrenoleukodystrophy is caused by a mutation in the ABCD1 gene that provides instructions to produce the adrenoleukodystrophy protein (ALDP). This gene produces an enzyme that assists in the metabolizing (break down) of certain fats. If this enzyme is missing, the fats accumulate in the brain.

If the disease is not treated, a person will experience damage to vision, hearing, coordination, and cognition and death may occur within ten years after initial symptoms.

 About the Lentivirus

The virus suspected as the probable cause for the current Phase 3 hold is called a lentivirus. Bluebird researchers suggest that this issue may not occur again as the researchers included a unique feature in the current Phase 3 trial.

Lentiviruses deliver a generous amount of genetic data into the DNA of the host cell. This makes the lentivirus a highly efficient delivery vector. Although another form of gene-delivering virus (vector) was suspected of causing cancer in other trials, a lentivirus has never been implicated.

About Myelodysplastic Syndrome

One year after the treatment in connection with the current Phase 3 trial, a participant was diagnosed with myelodysplastic syndrome (MDS). It is a blood-cell disease known to be a precursor to leukemia.

In addition, two more participants who also received treatment were found to have bone marrow cell abnormalities that could possibly evolve into MDS according to one of Bluebird’s scientific officers.

A Known Risk

The risk of inserting genetic material into an individual’s genome and the chance of activating cancer in a nearby gene has been known for years. In the early 2000s, dozens of gene therapy trials associated with the retrovirus were halted by the FDA. During that period several patients had developed leukemia after treatment for an immune disorder.

As a result, scientists began using lentiviruses which are a subset of retroviruses.

A month ago Bluebird’s therapy was approved in Europe as a result of data from a previous trial involving thirty-two patients under the age of seventeen.

Although lentiviruses enjoy an excellent gene therapy track record, just recently two sickle cell trials were interrupted by Bluebird due to one patient developing MDS. These trials also used lentiviruses. The trials were reconvened after new studies determined it was not likely that the lentiviruses caused the MDS.

In the new case involving lentiviral DNA, researchers discovered that in previous trials the lentiviral DNA had been inserted into the genome using mouse-derived retroviruses. This was an indication to the researchers that the viral DNA could have activated stem cells causing them to multiply abnormally.

An officer of Bluebird explained that the vector identified in this trial is known as a promotor. It assists in turning on the therapeutic gene. The promoter that is being used for this trial has broad activity reaching all genes of any cell type at the point of insertion. This includes stem cells. Usually, promoters only activate genes in specific forms of mature blood cells.

The first step in the gene therapy is to collect the patient’s own stem cells from the bone marrow. The collected cells are treated in a dish together with the lentivirus that carries a healthy version of the ABCD1 gene. Prior to the lentivirus treatment chemotherapy is administered in order to destroy cells remaining in the bone marrow.

A consultant for Bluebird bio who assisted in the design of the viral vector explained that brain cells needed to produce high levels of ALDP in order to treat the disease. However, this maneuver risked activating cancer genes in close proximity to the vector. There do not seem to be gene therapies that are lentivirus-based using this form of promoter. Other promoters have been identified that have less risk of cancer.

Looking Forward

Bluebird has plans to finish its submission to the FDA in 2021 pending the outcome of the hold. The company emphasizes the benefits of lentivirus-based therapies that have treated over three hundred patients with various medical conditions. There is also the fact that alternative treatments currently available carry certain risks. The company’s findings may help researchers and scientists find improved vectors for use in the future.

Rose Duesterwald

Rose Duesterwald

Rose became acquainted with Patient Worthy after her husband was diagnosed with Acute Myeloid Leukemia four years ago. He was treated with a methylating agent While he was being treated with a hypomethylating agent, Rose researched investigational drugs being developed to treat relapsed/refractory AML.

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