INTERNET MULTICENTER THERAPEUTIC TRIALS OF X LINKED ADRENOLEUKODYSTROPHY

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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. Dr Moser's research programs relate mainly to X-Linked Adrenoleukodystrophy (X-ALD) and concern all aspects of this disorder, ranging from molecular biology, to animal models, clinical diagnosis, and therapeutic protocols. Our laboratory has been concerned with this disease for more than twenty years, has identified more than five thousand patients, and is considered a national and international resource for the study and therapy of X-ALD. MRI and MRS are crucial for the diagnosis of X-ALD, and also for basic studies of pathogenesis, both in patients and in a mouse model of this disease, and in addition are absolutely essential to decisions about therapeutic interventions and to their evaluation. X-ALD causes demyelination and axonal damage, which lead to progressive neurological disability and eventually to death. It presents diagnostic and therapeutic challenges because of striking and unpredictable variations in phenotypic expression. The phenotype ranges fr om the chi ldhood cerebral form which leads to total disability and often to death by ten years of age, to milder adult forms, which at the other extreme may be compatible with survival to the eight's decade with only moderate disability. The various phenotypes often co-occur in the same family and do not correlate with the nature of the mutation or the severity of the biochemical deficit. MRI and MRS have been found to be the most valid predictors of clinical course and the evaluation of therapy. The MRI abnormalities often shown characteristic patterns. Brain MRI abnormalities precede the development of neurological symptoms. Studies in our lab have shown that MRS is an even more sensitive predictor of neurological involvement. Recent studies by Pouwels et al. indicate that quantitative spectroscopy with focus on the choline and myoinositol peaks help to determine whether demyelination is in an active or quiescent stage, and these approaches are now being utilized and extended at the F.M. K irby Center. The advances in MR spectroscopy techniques, being developed in Project 2 of your Resource are of critical importance to this program. At the clinical level MRI and MRS are essential for the decision whether a patient should receive a bone marrow transplant. This procedure is effective under carefully defined circumstances, but carries a high risk and should not be offered to patients who do not need it, or are too disabled to benefit from it. Recent advances, including MRS and magnetization transfer techniques are of key importance to this decision. The study supported by the FDA and the Multicenter Clinical Trial for which NIH funding for is requested in our application to be submitted on October 1, involve the evaluation of therapeutic interventions. MRI and MRS are key to these evaluations and will be assisted greatly through the Contract with the National Library of Medicine. In this contract the "next generation internet" will be utilized to transmit images from all parts of the world to the F.M. Kirby Center, where they will be evaluated in the Kirby Center. In addition to these clinically oriented applications, Project 2 will be applied to enhance understanding of the pathogenesis of X-ALD in patients. These studies of pathogenesis will include comparisons with neuropathological and neurophysiological alterations as well as examination of the effects of BMT and pharmacological therapies. In addition to MRS, the present studies will also employ connectivity testing using the methodology developed in TRD3. A first result was shown in the recent paper by Mori et al., MRM 2002.