MAGNETIC FIELD & APPLICATION FOR MR SUSCEPTIBILITY QUANTIFICATION

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We are developing a number of strategies for monitoring gene therapy. The first approach is to monitor the specific phenotype of the genetic disease. For example, in mucopolysaccharidosis type VII (MPS VII) the genetic defect is failure to produce -glucuronidase. We are synthesizing glucuronides of fluorinated phenols. When the glycosidic bond is cleaved by -glucuronidase , the 19F chemical shift of the liberated phenol is expected to change by about 10ppm; furthermore, since the liberated fragment is anionic, it is expected to be trapped in the cell. In cystic fibrosis the genetic defect is in the chloride transporter (CFTR). This is known to result in an increase in the sodium and chloride concentrations in air passage fluids. We, therefore, are developing multiple quantum 23Na methods to detect and quantitate this alteration in sodium concentration. In hypercholesteremia the genetic defect is the lack of LDL receptors. We are developing methods to label LDL mole cules with magnetite so that delivery of LDL to liver lysosomes could be detected by MRI. These examples demonstrate how magnetic resonance methods can be developed to monitor genetic defects in enzymes, ion transport and receptors. However, we recognize that development of methods to monitor phenotypes of genetic defects will required an immense amount of effort and will not be completely reliable since similar genotypes may be expressed as different phenotypes or may be expressed to different extents. A more general approach is to develop a suitable marker gene that could be attached to the transfection vector and expressed by the same promotor. An ideal marker for MRI detection would be magnetite, which increases the relaxivity of water, which is 110 M in protons. Magnetite also has about a thousandfold higher relaxivity than an equivalent amount of iron (such as if found in the iron core of ferritin). Certain bacteria have the unique ability to produce magnetite from iron. T he protein responsible for this activity has been cloned and expressed in both bacterial and mammalian cells. We are exploring the utility of this protein as a marker for gene therapy.