International consensus guidelines recommend that all boys and men with ALD be monitored by MRI for the development of cerebral ALD even in the absence of neurological symptoms. Monitoring is crucial to preserve the best chances for a good outcome, as treatment options are most successful when pursued at the early stages of cerebral ALD progression. Current guidelines suggest that a baseline MRI should be obtained at the age of two, and twice yearly MRIs spaced out every 6 months should be conducted between the ages of two and 12 (as these are the ages with the highest risk to develop cerebral ALD). From 12 years onward, screening should continue annually, including in adulthood. Since the development of cerebral ALD is extremely rare in girls and women with ALD, regular monitoring is not currently recommended for females.
Once a boy is diagnosed with cerebral ALD, it is crucial to undergo prompt evaluation in order to evaluate eligibility for transplant or gene therapy. It is crucial for a boy to undergo transplant at the earliest signs of the disease. Doctors will often use the Loes Score determined from MRI in combination with exams to determine if a patient is likely to benefit from a transplant.
Allogeneic hematopoietic stem cell transplant (Allo-HSCT), also known as bone marrow transplant (BMT), has long been used for eligible boys with cerebral ALD to halt disease progression. Hematopoietic stem cells are special cells found in bone marrow that grow or mature into different types of cells. In allogeneic stem cell transplantation, affected individuals receive hematopoietic stem cells from a healthy person, referred to as a donor. Donors can be either family members or unrelated donors with compatible human leukocyte antigens (HLA) markers in their blood. The healthy cells will produce the ALD protein that the patient with cerebral ALD is incapable of making. A series of studies conducted over the last two decades have shown that a BMT stops the progression of neurological disease in ALD, although it does not improve adrenal insufficiency.
Gene therapy is an alternative to Allo-HSCT. Gene therapy involves removing a patient’s bone marrow cells from their body and editing them in the lab so that the cells become capable of producing the ALD protein. After the patient’s cells are processed, they are re-introduced to the patient in a similar process as the traditional bone marrow transplant. On September 16, 2022, the U.S. Food and Drug Administration (FDA) granted Accelerated Approval of the gene therapy product SKYSONA® (elivaldogene autotemcel), also known as eli-cel, to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Read the press release.
Both traditional Allo-HSCT and gene therapy have risks and benefits. The decision of which therapy to pursue should be a conversation between a family and their doctors, and may depend on a variety of factors. These therapies are not offered unless a boy has cerebral ALD.
Men with AMN who develop cerebral ALD may be eligible for an Allo-HSCT depending on a number of factors, and should consult with their doctors right away to determine the risks and benefits to transplant. At this time, gene therapy is only available for boys age 4-17, and is not a treatment option for men with cerebral ALD. Men with cerebral ALD may also be eligible for CALYX clinical trial, which aims to assess the efficacy and safety of leriglitazone in adult men with cerebral ALD. See below for additional information.
