Replacement therapy for inherited enzyme deficiency - macrophage-targeted glucocerebrosidase for Gaucher's disease

Article Abstract:

Gaucher's disease is a lysosomal storage disorder. Normally, the tiny lysosomes within a cell serve to degrade and recycle various cellular components as well as some materials imported from outside the cell. In Gaucher's disease, the lysosomes are deficient in a particular enzyme called glucocerebrosidase. The consequences of this enzyme deficiency are seen mainly in the lysosomes of macrophages, the large blood cells that digest both bacteria and normal cellular debris. Since the enzyme is lacking, a very special type of fat called a sphingolipid can not be broken down and it accumulates within the lysosome. Ultimately, many organs of the body become affected, and the normal cells of the bone marrow are progressively displaced by macrophages with excess fat they can do nothing with. Most patients develop anemia, enlargement of the internal organs, and skeletal abnormalities. A few patients develop neurologic abnormalities as well. One approach to treating such a disease would be to give the patient large amounts of the enzyme glucocerebrosidase. This has been attempted with variable results. However, the fact that the major defect is in the lysosomes of the macrophages allows for a therapeutic approach not possible in other genetic disorders. If the enzyme could be altered in such a way that the macrophages would eat it, as they do many foreign particles, then the macrophages themselves would place the enzyme exactly where it belongs. This approach was tried in the treatment of 12 patients with Gaucher's disease. The patients were treated with the chemically modified enzyme to enhance the likelihood its accumulation within macrophages. After three to four months of twice-weekly infusions of the enzyme, all 12 patients experienced an improvement in their anemia. The platelet count, an indicator of normal blood clotting, increased in seven patients. During the course of the study, many of the observed symptoms were decreased, including bone pain, easily bruising, and chronic fatigue. The long-term treatment with the enzyme was well tolerated by the patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Care and treatment, Physiological aspects, Lipid metabolism disorders

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Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources

Article Abstract:

Genetically engineered glucocerebrosidase appears to be as effective in treating Gaucher's disease as the naturally occurring version of the enzyme. Gaucher's disease is an inherited enzymatic deficiency of fat metabolism that that adversely affects blood chemistry. Fifteen patients with moderate to severe Gaucher's disease were randomly assigned to receive Ceredase, an enzyme extracted from human placentas, and 15 patients were treated with Cerezyme, a genetically engineered enzyme. Similar improvements were seen in both groups in hemoglobin levels and shrinkage of enlarged livers and spleens. Improvements in platelet counts were minimal. Forty percent of the Ceredase group formed antibodies to the enzyme versus 20% of the Cerezyme group, although no allergic symptoms developed. Cerezyme has the advantages of being available in uncontaminated form in theoretically unlimited amounts. Extracting and purifying the enzyme from placentas would require tons of placentas per year per patient.

Drug therapy, Genetic engineering

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A 21-year-old African woman with thoracolumbar pain and fever

Article Abstract:

A 21-year-old woman from Africa with pain in her middle and lower back and a fever was found to have tuberculosis in her vertebrae. X-rays and radiographic scans showed bone destruction and a mass where her 11th rib connected to her spinal column. A fine-needle aspiration of the area was positive for Mycobacterium tuberculosis. The woman received antibiotics and a back brace. Seven months after the beginning of treatment her back pain was almost gone and she had no neurologic problems. Tuberculosis is common in parts of Africa and, in cases that do not involve the lungs, it often invades bones. Such infections often affect the spinal column and spread to the surrounding tissue. Diagnosis may be made with a fine-needle aspiration, which is safer than an open biopsy. The disease may be treated with antitubercular antibiotics, often without the need for surgery.

Diagnosis, Tuberculosis

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