61
lysosomes is associated with each disorder. This results in accumulation of macromolecules in lysosomes, thereby causing enlargement of cells carrying lysosomes
and eventually leading to organ dysfunction. Lysosomal storage diseases are genetic
disorders either due to autosomal recessive inheritance or X-linked inheritance,
which causes dysfunction or reduced activity of specific lysosomal enzymes. LSDs
includes Gaucher disease types 1 and III, Fabry disease, Mucopolysaccharidosis
Type I (Hurler, Hurler/Scheie Syndrome), Mucopolysaccharidosis Type II (Hunter
Syndrome), Mucopolysaccharidosis Type VI, (Maroteaux-Lamy Syndrome) and
Pompe disease.
Christian de Duve was the first to propose the concept of enzyme replacement
therapy for lysosomal storage disorders and it was later experimentally supported
(De Duve 1966). Though it was proposed during the 1960s its clinical use was not
in practice until 1991. Alglucerase (Ceredase
®
) was the first enzyme for replacement therapy approved by the USFDA in 1991 against a lysosomal storage disease
(Gaucher disease).
2.6.1 Gaucher Disease
Gaucher disease is an inherited disease characterized by a defect of lack of glucocerebrosidase enzyme resulting in glucocerebroside accumulation in lysososmes.
The lipid-accumulated cells are called Gaucher cells and found in liver, spleen,
bone marrow and lung. This makes it a multi-organ disorder. The disease is characterized by hepatosplenomegaly (enlargement of liver and spleen) and skeletal complications. Gaucher disease is classified into three types based on clinical
manifestations. In Type I-non-neuronopathic (adult), the central nervous system is
not involved. But in the case of Type II-acute neuronopathic (infantile) and Type
III-subacute neuronopathic (juvenile) the central nervous system is involved. Most
common among them are Type 1 where the central nervous system is not involved.
Disease control is either by enzyme replacement therapy (ERT) or substrate reduction therapy. Enzyme replacement therapy was found to be successful in managing
Gaucher disesase. As mentioned previously, enzyme replacement therapy was first
established for the treatment of Gaucher disease where Alglucerase (Ceredase
®
), a
placental-derived enzyme glucocerebrosidase, was used. ERT reversed symptoms
of Gaucher disease. It was later replaced by recombinant glucocerebrosidase
(Imiglucerase, Cerezyme
®
) in 1994. Two other recombinant enzymes, namely velaglucerase alfa (VPRIV
®
), which received FDA approval in 2010, and taliglucerase
alfa (Elelyso
®
), which received FDA approval in 2012, are also available for
ERT. The recombinant enzymes differ from each other in terms of source.
Imiglucerase is obtained from Chinese hamster ovary (CHO) cell line, velaglucerase alfa is isolated fromm human cells, and taliglucerase alfa is obtained from
carrot cells and shows similar effectiveness (Elstein 2011). Imiglucerace has been
in use for a longer period and only 1% of patients develop adverse reactions to imiglucerase ERT (Zimran et al. 2011) (Fig. 2.10).
2 Therapeutic Enzymes
lysosomes is associated with each disorder. This results in accumulation of macromolecules in lysosomes, thereby causing enlargement of cells carrying lysosomes
and eventually leading to organ dysfunction. Lysosomal storage diseases are genetic
disorders either due to autosomal recessive inheritance or X-linked inheritance,
which causes dysfunction or reduced activity of specific lysosomal enzymes. LSDs
includes Gaucher disease types 1 and III, Fabry disease, Mucopolysaccharidosis
Type I (Hurler, Hurler/Scheie Syndrome), Mucopolysaccharidosis Type II (Hunter
Syndrome), Mucopolysaccharidosis Type VI, (Maroteaux-Lamy Syndrome) and
Pompe disease.
Christian de Duve was the first to propose the concept of enzyme replacement
therapy for lysosomal storage disorders and it was later experimentally supported
(De Duve 1966). Though it was proposed during the 1960s its clinical use was not
in practice until 1991. Alglucerase (Ceredase
®
) was the first enzyme for replacement therapy approved by the USFDA in 1991 against a lysosomal storage disease
(Gaucher disease).
2.6.1 Gaucher Disease
Gaucher disease is an inherited disease characterized by a defect of lack of glucocerebrosidase enzyme resulting in glucocerebroside accumulation in lysososmes.
The lipid-accumulated cells are called Gaucher cells and found in liver, spleen,
bone marrow and lung. This makes it a multi-organ disorder. The disease is characterized by hepatosplenomegaly (enlargement of liver and spleen) and skeletal complications. Gaucher disease is classified into three types based on clinical
manifestations. In Type I-non-neuronopathic (adult), the central nervous system is
not involved. But in the case of Type II-acute neuronopathic (infantile) and Type
III-subacute neuronopathic (juvenile) the central nervous system is involved. Most
common among them are Type 1 where the central nervous system is not involved.
Disease control is either by enzyme replacement therapy (ERT) or substrate reduction therapy. Enzyme replacement therapy was found to be successful in managing
Gaucher disesase. As mentioned previously, enzyme replacement therapy was first
established for the treatment of Gaucher disease where Alglucerase (Ceredase
®
), a
placental-derived enzyme glucocerebrosidase, was used. ERT reversed symptoms
of Gaucher disease. It was later replaced by recombinant glucocerebrosidase
(Imiglucerase, Cerezyme
®
) in 1994. Two other recombinant enzymes, namely velaglucerase alfa (VPRIV
®
), which received FDA approval in 2010, and taliglucerase
alfa (Elelyso
®
), which received FDA approval in 2012, are also available for
ERT. The recombinant enzymes differ from each other in terms of source.
Imiglucerase is obtained from Chinese hamster ovary (CHO) cell line, velaglucerase alfa is isolated fromm human cells, and taliglucerase alfa is obtained from
carrot cells and shows similar effectiveness (Elstein 2011). Imiglucerace has been
in use for a longer period and only 1% of patients develop adverse reactions to imiglucerase ERT (Zimran et al. 2011) (Fig. 2.10).
2 Therapeutic Enzymes