Stem Cell Treatment Fails to Help 2 Boys with Advanced Cerebral ALD

Stem Cell Treatment Fails to Help 2 Boys with Advanced Cerebral ALD

An infusion of anti-inflammatory mesenchymal stem cells (MSC) given two boys with the cerebral form of adrenoleukodystrophy failed to halt or prevent disease progression, a case study reported. 

Whether the advanced status of their disease or an inadequate dose of cells was the reason for the failure is not known, its authors said.

The report, “Failure of intrathecal allogeneic mesenchymal stem cells to halt progressive demyelination in two boys with cerebral adrenoleukodystrophy,” was published in the journal Stem Cells Translational Medicine.

A neuroinflammatory process known as cerebral adrenoleukodystrophy, or CALD, occurs in up to 40% of boys with ALD between 4 and 10 years old. This neuroinflammation is characterized by the presence of many types of immune cells that normally fight infections, as well as autoantibodies that target healthy tissues. 

Mesenchymal stem cells (MSCs) are a type of stem cell, commonly found in the bone marrow, with the ability to become a variety of cell types, including bone, cartilage, muscle, and fat cells. 

MSCs have been studied for their anti-inflammatory properties in a wide variety of medical conditions, and improvements in some treated patients are known. These cells also have a variety of tissue repair- and cell growth-promoting properties. 

Given that CALD is caused by neuroinflammation, a team led by researchers based at the University of Minnesota wondered if MSCs could counter the inflammation and slow the progress of the disease. 

The team tested their hypothesis on two boys with advanced CALD, who were no longer eligible for early hematopoietic cell transplant — a transfusion of stem cells able to become blood cells; this type of cell transplant is known to arrest CALD progression if used early in the disease course. 

The first boy, known as D.H., came to the attention of medical professionals at age 5, after he began losing his vision and hearing. 

Magnetic resonance imaging (MRI) of his brain revealed a hallmark of CALD known as demyelination — the loss of the protective myelin sheath surrounding nerve cells. Blood tests showed elevated very-long-chain fatty acids (VLCFAs) in his blood, also a disease hallmark, and adrenal function testing was consistent with advanced CALD. 

Before the MSC infusion, the boy was given the steroid hydrocortisone, the pain reliever acetaminophen, and the antihistamine diphenhydramine. He then received three weekly doses of MSCs (isolated from another person) via intrathecal (IT) injection — treatment into the fluid-filled space between tissue layers that cover the spinal cord and brain.

An MRI performed two months after the last IT injection showed demyelination, and signs of disease progression. An analysis of the cerebrospinal fluid (CSF) after two weeks, and again at two months, found no change in any parameter. 

The second boy (A.S.), age 7, experienced normal growth and development until 6 months prior to his diagnosis. He began to develop difficulties completing math assignments, had spatial disorientation, and problems with balance and walking.

A brain MRI showed extensive demyelination, he had elevated VLCFAs levels, and a mutation in the ABCD1 gene, all confirming advanced CALD. 

Similar to D.H., this boy was also given medications were given prior to the MSC infusion. However, A.S. was only given one MSC treatment, after an analysis of the cells found they had acquired a chromosomal abnormality during their expansion in the lab. 

An MRI performed one month after the MSC infusion showed no change in demyelination, indicating that the disease was not in remission. 

Given the results, in both cases further treatment was not offered.

“The delivery of MSCs intrathecally was safe and well tolerated,” the researchers wrote, but “unfortunately, neither patient showed any reversal or arrest in the progression of disease as assessed by MRI studies.”

“Whether this was because of the rapidly progressive nature of their disease or other factors such as lack of adequate cell dosing is unknown, and future studies should focus on these factors,” they added.