The Leukodystrophy Research Laboratory is located in the MGH Neuroscience Center and is involved in both basic and clinical/translational research.
MR Imaging Studies
The Martinos Center for Biomedical Imaging provides a unique resource and opportunity for leukodystrophy patients. Advanced MR imaging is used to establish new biomarkers and understand mechanisms of disease progression.
Genetics
In partnership with the Center for Human Genetic Research (CHGR) we are pursuing molecular genetic strategies to identify the underlying DNA sequence variations (genotypes) that modify the disease course in leukodystrophies.
Clinical trials
Aspects of neurodegeneration vary from one leukodystrophy to another, specific to the differing genetic and metabolic defects present in each leukodystrophy. Since cell death occurs by different mechanisms and involves different cell types, it is important to differentiate what cells are affected as well as the molecular pathways in order to bring effective treatments. Current research in the Leukodystrophy Clinic is examining disease mechanisms and is supported by NIH in this effort. Clinical trials building on the insights of these studies are currently in development (immunomodulation, gene therapy, etc.).
Our researchers work closely with the Cecil B. Day Laboratory for Neuromuscular Research (Day Lab). There is a strong emphasis on neurodegeneration at MGH as exemplified by the MassGeneral Institute for Neurodegenerative Disease (MIND). Collectively, we are in unique position to advance the field.
Specific genetic and metabolic abnormalities that alter the lipids of the nervous system pose a particular challenge that can be addressed with multiple resources. Insights into lipid metabolism promise to bear on the advancement of all neurodegenerative diseases. Collaborative efforts enhance our efforts.
Research Summaries
Leukodystrophy research at MGH is primarily focused upon X-linked adrenoleukodystrophy (X-ALD) and metachromatic leukodystrophy (MLD).
Leukodystrophy research at MGH is primarily focused upon X-linked adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy (MLD) and Tay-Sachs Disease. There are four main areas of interest:
1. Novel Therapies for X-ALD.
The primary defect in X-ALD is the loss of normal ABCD1 protein. We are interested in two different strategies to correct this problem. One approach is to deliver a normal version of the gene to the brain. This can be accomplished through modification of viruses. The virus is stripped of many of its genetic components that allow it to grow normally. Then, engineer in the DNA necessary to make the correct ABCD1 protein. These viruses can then be injected into mice that lack the ABCD1 gene. The belief is that if we can correct the disease-related changes in the mice with these viruses, then we may be able to deliver the same to patients some day.
The second approach is to find ways to increase expression of other proteins in the cell that could do the job that ABCD1 normally would do. One such candidate is the related protein ABCD2. Other groups have shown that increasing the amount of ABCD2 in mice lacking ABCD1 corrects many of their deficits. This research is being conducted in close collaboration with the Day Laboratory for Neuromuscular Research.
2. Neuroimmunology of X-ALD.
A distinct feature of adrenoleukodystrophy that sets it apart from other leukodystrophies is the prominent inflammatory reaction. Correlation of clinical and pathologic findings indicates that the progression in cerebral X-ALD is related to the perivascular infiltration of lymphocytes in the brain white matter. It is hypothesized that variations in lipid composition render myelin prone to immunologic attack, leading to demyelination and subsequent axonal loss. We are currently examining the known ALD mouse model regarding its reaction to proinflammatory triggers. Further we are examining inflammatory markers on ALD brain tissue samples.
3. Imaging the Pathophysiology of X-ALD.
MRI abnormalities in X-ALD patients most often precede onset of neurologic symptoms but given the rapid progressive course only precede death by one to two years. ALD patients with cerebral involvement show white matter lesions that are characteristic in respect to location and attenuation pattern. We are conducting research in collaboration with the Martinos Center of Biomedical Imaging in order to develop biomarkers of cerebral involvement in ALD. Our prior research has demonstrated that MR spectroscopy predicts disease progression in ALD. Biochemical changes in the normal appearing white matter herald lesion development and thus help decide on the importance of therapeutic interventions.
4. Natural History of MLD.
The MGH Leukodystrophy Clinic participates in the international MLD patient registry and actively contributes to the understanding of the natural history of MLD. Our clinical research is focused on the evolution of clinical symptoms and MRI lesion progression in MLD. The Martinos Center for Biomedical Imaging and the Center for Morphometric Analysis are assisting in this effort. With the prospect of novel therapies (enzyme replacement therapy, gene therapy) this data will be vital information for patients and physicians to weigh the risks and benefits of treatment options.
5. Gene Therapy Study for Tay-Sachs Disease
The Leukodystrophy Clinic is part of the Tay Sachs Gene Therapy Consortium, an international collaborative group of scientists committed to translating current results from animal experiments into a human clinical trial. See www.tsgtconsortium.com
Publications
Eichler F, Van Haren K. Immune response in leukodystrophies. Pediatric Neurology. 2007;37(4):235-44.
Eichler FS, Mahmood A, Loes D, Bezman L, Lin D, Moser HW, Raymond GV. Magnetic Resonance Imaging Detection of Lesion Progression in Adult Patients With X-linked Adrenoleukodystrophy. Archives of Neurology. 2007;(64):659-664.
Eichler F, Tan WH, Shih VS et al. Proton MR Spectroscopy and Diffusion Weighted Imaging in Isolated Sulfite Oxidase Deficiency. Journal of Child Neurology 2006: 2006 Sep;21(9):801-5.
Tan WH, Eichler F, Hoda S et al. Isolated Sulfite Oxidase Deficiency: A Case Report With a Novel Mutation and Review of the Literature. Pediatrics 2005 Sep;116(3):757-66.
Eichler F, Barker PB, Cox C, Edwin D, Ulug AM, Moser HW, and Raymond G. Proton MR Spectroscopic Imaging predicts lesion progression on MRI in X-linked Adrenoleukodystrophy. Neurology 2002;58:901-907.
Eichler F, Itoh R, Barker PB, Mori S, Garrett ES, van Zijl PC, Moser HW, Raymond GV, Melhem ER. Proton MR spectroscopic and diffusion tensor brain MR imaging in X-linked adrenoleukodystrophy: initial experience. Radiology. 2002 Oct;225(1):245-52.
O’Neill GN, Aoki M, Brown RH Jr. ABCD1 translation-initiator mutation demonstrates genotype-phenotype correlation for AMN. Neurology. 2001 Dec 11;57(11):1956-62.