Biomedical Engineering Reference
In-Depth Information
fi brosis patient resulted in a signifi cant reduction of the sputum's viscosity. Clinical trials also
showed the product to be safe and effective, and Genentech received marketing authorization for
the product in December 1993, under the tradename Pulmozyme. The annual cost of treatment
varies, but often falls between US$10 000 and US$15 000.
Pulmozyme is produced in an engineered CHO cell line harbouring a nucleotide sequence coding
for native human DNase. Subsequent to upstream processing, the protein is purifi ed by tangential
fl ow fi ltration followed by a combination of chromatographic steps. The purifi ed 260 amino acid
glycoprotein displays a molecular mass of 37 kDa. It is formulated as an aqueous solution at a concen-
tration of 1.0 mg ml
1
, with the addition of calcium chloride and sodium chloride as excipients. The
solution, which contains no preservative, displays a fi nal pH of 6.3. It is administered directly into the
lungs by inhalation of an aerosol mist generated by a compressed-air-based nebulizer system.
12.5.3 Glucocerebrosidase
Glucocerebrosidase preparations are administered to relieve the symptoms of Gaucher's disease,
which affects some 5000 people worldwide. This is a lysosomal storage disease affecting lipid me-
tabolism, specifi cally the degradation of glucocerebrosides. Glucocerebrosides are a specifi c class
of lipid, consisting of a molecule of sphingosine, a fatty acid and a glucose molecule (Figure 12.15).
They are found in many body tissues, particularly in the brain and other neural tissue, in which
they are often associated with the myelin sheath of nerves. Glucocerebrosides, however, are not
abundant structural components of membranes, but are mostly formed as intermediates in the
synthesis and degradation of more complex glycosphingolipids. Their degradation is undertaken
by specifi c lysosomal enzymes, particularly in cells of the reticuloendothelial system (i.e. phago-
cytes, which are spread throughout the body and which function as (a) a defence against microbial
infection and (b) removal of worn-out blood cells from the plasma; these phagocytes are particu-
larly prevalent in the spleen, bone marrow and liver).
Gaucher's disease is an inborn error of metabolism characterized by lack of the enzyme glu-
cocerebrosidase, with consequent accumulation of glucocerebrosides, particularly in tissue-based
macrophages. Clinical systems include enlargement and compromised function of these mac-
rophage-containing tissues, particularly the liver and spleen, as well as damage to long bones
and, sometimes, mental retardation. Administration of exogenous glucocerebrosidase as enzyme
replacement therapy has been shown to reduce the main symptoms of this disease. The enzyme is
normally administered by slow i.v. infusion (over a period of 2 h) once every 2 weeks.
CH
2
OH
O
CH
3
(CH
2
)
12
CH
CH
CH
CH
CH
2
O
HO
OH
NH
OH
C
OH
O
R
Figure 12.15
Generalized structure of a glucocerebroside
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