New Advancements for ALD
New Advancements for Boys with Adrenoleukodystrophy (ALD).
Boys with Adrenoleukodystrophy (ALD), a rare x-linked disorder caused by mutations within the ABCD1 gene, are unable to metabolize very long chain fatty acids (VLCFA). This leads to an accumulation of VLCFA in the blood, adrenal glands, testes and brain. In approximately 40 percent of cases, accumulation of VLCFA causes acute inflammatory demyelination in the brain, termed cerebral ALD (cALD). Most of the time, this occurs between 4 and 10 years of age but may occur later. Boys with cALD develop normally until disorder onset, which can be characterized by rapidly progressive loss of visual, auditory, motor and cognitive function. If left untreated, childhood onset cALD is generally fatal within a few years.
Allogeneic blood and marrow transplant (BMT) is currently the only treatment definitively shown to stop disorder progression in cALD. Transplant is accomplished by the infusion and engraftment of healthy donor blood stem cells that can proliferate and migrate to the brain. The exact mechanism of action of BMT in cALD remains poorly understood. While allogeneic BMT offers the best treatment for cALD at this time, limitations of transplant remain.
Though BMT is clearly indicated for early stage cALD patients with absent or mild neurologic impairment, it is difficult to predict which patients with more advanced disease could benefit from transplant. Patients with moderate cerebral disease demonstrate variable neurologic outcomes following BMT. An ongoing study at the University of Minnesota aims to analyze pre-transplant biomarkers of disease severity, in hopes that one or more may ultimately be useful in prognosticating the utility of BMT for patients with more advanced disease.
Researchers suspect that inflammation in the brain may play an important role in predicting post-BMT outcomes for moderately advanced cALD. For this reason, another study will use advanced neuro-imaging techniques that aim to quantify neuro-inflammation in hopes that this disease characteristic may ultimately be useful in prognosticating post-transplant outcomes.
Current research at the University of Minnesota is exploring ways to preserve cognitive function and improve outcomes for cALD patients who undergo BMT. Because of inflammation and oxidative stress present in the brains of cALD patients, the central nervous system is especially sensitive to the chemotherapy used in pre-transplant conditioning regimens. The University of Minnesota was the first to show that the addition of high-dose anti-oxidant therapy in the peri-transplant period improved survival of boys with moderate to advanced cALD. Ongoing clinical trials aim to determine the best approaches to antioxidant and anti-inflammatory therapies for the future.
A new multi-center, international trial opening soon at the University of Minnesota will use gene therapy in combination with autologous BMT to treat boys affected by cALD. The hope is that this new approach will provide the benefits of BMT without the associated complications of allo-immunity, such as graft rejection and graft-versus-host disease. Click here to read more about this exciting new clinical trial.
Our comprehensive care team-including world-renowned specialists in BMT, neurologists, endocrinologists, neuropsychologists and genetic counselors is available for assessment and consultation. The team works together to create an individualized monitoring and treatment plan for boys with ALD and female carriers. To learn more about the Inherited Metabolic Disorders Comprehensive Care Program at University of Minnesota Masonic Children’s Hospital, contact Paul Orchard, MD, Weston Miller, MD, Troy Lund, MD, or call Patty Kleinke with the BMT Program office at 612-273-0857 or 888-601-0787 (toll free).