Central nervous system tissue replacement

When certain enzymes involved in the hydrolytic or oxidative breakdown of cellular lipids are absent from tissues, their lipid substrates tend to accumulate, resulting in a lipid storage disease or lipidosis. All are rare but the most important involve the accumulation of glycosphingolipids in the central nervous system. Enzyme replacement therapy is now becoming a practical possibility in some cases. 

The classic example of this approach involves the use of levodopa (l-3,4-dihydroxyphenylalanine, Figure 8.13) to treat Parkinson s disease [58]. Parkinson s disease is distinguished by the marked depletion of dopamine— an essential neurotransmitter—in the basal ganglia. Direct dopamine replacement is not possible, because dopamine does not permeate through the blood-brain barrier. However, the metabolic precursor of dopamine, levodopa, is transported across brain capillaries by the neutral amino acid transporter (see Table 5.5 and the related discussion). Peripheral administration of levodopa, therefore, produces an increase in levodopa concentration within the central nervous system some of these molecules are converted into dopamine due to the presence of decarboxylate enzymes in the brain tissue, but decar-boxylate activity is also present in the intestines and blood. To prevent conversion of levodopa into dopamine before entry to the brain, levodopa is usually administered with decarboxylase inhibitors. 

Cells which are undergoing frequent division, and organs and tissues in which the cells are replaced slowly, exhibit high radiation sensitivity. Of the some 200 different kinds of cells in our body, some never divide (e.g. in the ovary, some sense organs and part of the central nervous system, except in the embryo state), while others divide frequently (bone marrow, intestinal epithelium, male gonads). The cell cycle time varies from hours to days. Usually, tumor cells divide much faster (3-S times) than surrounding healthy tissue. 

In order to minimize the risks of sensitizing recipients to exogenous proteins, it is desirable to prepare enzymes for replacement therapy from human sources. The first treatment by such means was that of a patient with Sandhoff-Jatzkewitz disease where hexosaminidase A was infused intravenously. This experiment demonstrated three major problems in the use of enzyme therapy. Firstly, the infused enzyme tends to concentrate in tissues such as the liver, and other affected tissues may accumulate little. Secondly, the enzyme is subject to rapid turnover so that the administered enzyme has virtually disappeared from the recipient after 24 h. Thirdly, the administered enzyme cannot pass the blood-brain barrier so that lipidoses with central nervous system impairment are untreatable by this means (Brady, 1977). Tay-Sachs disease and Fabry s disease have been treated by enzyme replacement with limited success (cf. Brady, 1978). Better results have been obtained in the treatment of Gaucher s disease. A beneficial effect has been observed and the results are of impressive duration. Moreover, a high-yield large-scale procedure is now available for the isolation of human placental gluco-cerebrosidase (cf. Brady, 1978, for summary of clinical trials). 

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