PLACEBO-CONTROLLED STUDY OF X-ALD DIET THERAPY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose to conduct a double blinded placebo-controlled study of 4:1 Glyceryl Trioleate-Glyceryl Trierucate "Lorenzo's Oil" (LO) therapy in pure adrenomyeloneuropathy (AMN). AMN is one of the major phenotypes of X-linked adrenoleukodystrophy (X-ALD). X-ALD is due to a defect in ABCD1, a gene that codes for ALDP, a peroxisomal membrane protein. X-ALD is associated with the abnormal accumulation of saturated very long chain fatty acids (VLCFA) in plasma and tissues. Pure AMN is the form of X-ALD that manifests with slowly progressive paraparesis and sensory deficits. Its principal pathological change is a non-inflammatory distal axonopathy that involves the dorsal columns in the cervical segments and the corticospinal tract in the lower thoracic and lumbar segments. It affects most commonly young adult men, and less severely, middle aged or older women who are heterozygous for X-ALD. Approximately forty percent of all patients with X-ALD have this form of the illness. AMN stands in contrast to the rapidly progressive cerebral forms in which there is a rapidly progressive inflammatory disintegration of myelin. These are most common in childhood (Childhood Cerebral X-ALD, (CCER)), but they may manifest in adolescence or adults in patients who have AMN. Patients who have cerebral involvement in addition to pure AMN are referred to as "AMN cerebral." The oral administration of 4:1 glyceryl trioleate-glyceryl trierucate "Lorenzo's Oil" (LO) normalizes plasma VCLFA levels in X-ALD patients within four weeks. While earlier clinical trials had been disappointing, relatively long duration studies that were completed recently suggest that it is beneficial in two types of X-ALD: 1) as a preventive of neurological involvement in asymptomatic boys; and 2) pure AMN where it appears to slow progression. However, neither of these studies were controlled. We now propose a four-year placebo-controlled study to determine the effect of LO on the progression of pure AMN. The study will involve 100 adult men with pure AMN, and 100 adult women who are heterozygous for X-ALD and have pure AMN. Half of the patients will be studied at Johns Hopkins, the other half at the Massachusetts General Hospital. We request here GCRC support for the first year of the Hopkins component. Primary outcome measures will include standardized scales that have been validated for multiple sclerosis. An important novel part of the study is the utilization and validation of newly developed markers, namely quantitative tests of balance, sensation and motor function, and magnetic transfer imaging of the dorsal columns in cervical cord. Our preliminary studies suggest they may permit more sensitive and rapid assessment of the changes in spinal cord function and structure than can be achieved with current techniques, and this may facilitate and speed the evaluation of therapeutic intervention. They may also be applicable to the study of other spinal cord disorders. This study was initiated on Marcy 5, 2005. Forty-five patients (28 women and 17 men) have completed their 2-day baseline evaluation and are participating in the pro