There are three ways of altering the phenotype of a genetic disease so that it no longer harms an individual: restricting the substrate of a deficient enzyme, inhibiting a harmful metabolic reaction, or supplying a missing protein product.
restricting the substrate. Restricting the substrate of a deficient enzyme is the approach taken when a newborn is diagnosed with PKU. In this case, the deficient enzyme is phenylalanine hydroxylase, and the substrate is phenylala-nine. The infant's inability to break down the phenylala-nine in food leads to a buildup of the substrate, which causes the clinical symptoms. So the infant is immediately put on a special diet that contains only enough phenylalanine for immediate use. Lofenelac, a milk-based product that is low in phenylalanine, is fed to these infants just like formula. Later, certain fruits, vegetables, cereals, and noodles low in phenylalanine can be added to the diet. Meat, fish, eggs, dairy products, and bread, which contain high amounts of phenylalanine, must be avoided, especially during childhood, when brain development is most rapid. The artificial sweetener aspartame must also be avoided because it is made of two amino acids, one of which is phenylalanine.
People with PKU are generally advised to stay on a low-phenylalanine diet for life. Although maintaining these dietary restrictions may be difficult, it is effective. Numerous follow-up studies since newborn screening was initiated have shown that people with PKU who stay on the diet are no different from the rest of the population in terms of mental ability. This is an impressive achievement in public health, given the extent of mental retardation in untreated patients.
metabolic inhibitors. As we described earlier, people with familial hypercholesterolemia accumulate dangerous levels of cholesterol in their blood. These people are not only unable to metabolize dietary cholesterol, but also synthesize a lot of it. One effective treatment for people with this disease is the drug mevinolin, which blocks the patient's own cholesterol synthesis. Patients who receive this drug need only worry about cholesterol in their diet, and not about the cholesterol their cells are making.
Metabolic inhibitors also form the basis of chemotherapy for cancer. The strategy is to kill rapidly dividing cells, since rapid cell division is the hallmark of malignancy. But such a strategy is not selective for tumor cells. Many drugs kill dividing cells (Figure 17.19), but most of those drugs also damage other, non-cancerous, dividing cells in the body. Therefore, it is not surprising that people undergoing chemotherapy suffer side effects such as loss of hair (due to damage to the skin epithelium), digestive upsets (gut epithelial cells), and anemia (bone marrow stem cells). The effective dose of these highly toxic drugs for treating the cancer is often just below the dose that would kill the patient, so they must be used with utmost care. Often they can control the spread of cancer, but not cure it.
supplying the missing protein. An obvious way to treat a disease phenotype in which a functional protein is missing is to supply that protein. This approach is the basis of treatment of hemophilia, in which the missing blood clotting protein is supplied in pure form. The production of human clotting protein by recombinant DNA technology has made it possible for a pure protein to be given instead of crude blood products, which could be contaminated with the AIDS virus or other pathogens.
Unfortunately, the phenotypes of many diseases caused by genetic mutations are very complex. Simple interventions
5-Fluorouracil blocks the synthesis of nucleotides.
Etoposide prevents DNA from unwinding, blocking DNA replication and transcription.
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