An 8-year-old boy is brought to the office due to fatigue and intermittent bone pain for the past year. The patient's parents are concerned because he has stopped playing outside and mostly stays indoors watching television. On examination, height and weight are at the 5th percentile for age. The abdomen is soft and nontender with the liver palpable 4 cm below the right costal margin and the spleen palpable 8 cm below the left costal margin. Laboratory results show anemia and thrombocytopenia. A bone marrow biopsy shows macrophages with wrinkled, paperlike cytoplasm due to the accumulation of glycolipids within lysosomes. The patient is prescribed enzyme replacement therapy. Which of the following sets of pharmacologic properties best characterizes the administered medication?

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This patient has Gaucher disease, an autosomal recessive condition caused by a deficiency of lysosomal beta-glucocerebrosidase. This deficiency leads to the accumulation of glucocerebroside, a glycolipid component of cell membranes, within the lysosomes of macrophages, giving them the classic appearance of wrinkled tissue paper. Characteristic symptoms (eg, hepatosplenomegaly, pancytopenia, bone pain) develop as lipid-laden macrophages accumulate in the body's tissues (eg, spleen, liver, and bone). Lysosomal storage diseases can be treated through the delivery of a replacement enzyme into the lysosomes of affected cells; in the case of Gaucher disease, recombinant glucocerebrosidases (eg, imiglucerase) are available to replace the deficient enzyme. Almost all human enzymes, including lysosomal enzymes, are large polypeptides (eg, proteins) (Choice B). Although the oral route is often preferred for drug administration, most peptide-based drugs (eg, insulin, immunoglobulins) cannot be efficiently absorbed by the gastrointestinal tract due to the intestinal epithelial barrier and extensive proteolysis that takes place in the stomach and duodenum. As a result, large polypeptides such as a glucocerebrosidase must be administered intravenously to achieve adequate circulating levels. Once in the circulation, exogenous glucocerebrosidase can enter cells by binding to mannose 6-phosphate receptors. These receptors are found in the Golgi network, where they help route newly synthesized lysosomal proteins (tagged by mannose 6-phosphate residues). They are also expressed on the cell surface, where they bind free lysosomal enzymes that are accidentally secreted. Exogenous glucocerebrosidase can bind to these cell surface receptors, inducing endocytosis of the bound enzyme. It is then carried by endosomes to lysosomes, where it can degrade accumulated glucocerebrosides, reducing disease manifestations. (Choices C and D) Enzymes are large, polar polypeptides that are unable to effectively cross the cell membrane by passive diffusion. In contrast, steroid-based drugs are typically hydrophobic and can easily cross cell membranes by passive diffusion. However, steroidal drugs function by binding to receptors; they do not directly catalyze reactions. (Choices E, F, G, and H) Unlike in lysosomal storage diseases, enzyme replacement therapy for pancreatic exocrine insufficiency is administered orally because pancreatic digestive enzymes normally function within the gastrointestinal lumen. Educational objective: Certain lysosomal storage diseases, including Gaucher disease, can be treated with enzyme-replacement therapy (eg, recombinant glucocerebrosidase). Because enzymes are large proteins that cannot be orally absorbed, the replacement enzyme must be administered intravenously. Entry into the cell occurs by endocytosis after the replacement enzyme binds to mannose 6-phosphate receptors on the cell surface.

An 8-Year-Old Boy Is Brought to the Office Due to Fatigue