4. clinical applications of biopharmaceuticals - Enzymes Flashcards
this disease is from a defect in B and T lymphocytes that defend us from infection. this disease is inherited with as many as half of the cases linked to the X chromosome passed on by the mother. consists of three types:
1. a mutation in the interleukin 2 receptor gamma gene (IL2RG)
2. a mutation of JAK3 (chromosome 19), an important signalling molecule activated by IL2RG
3. a lack of enzyme adenosine deaminase (ADA), coded for by a gene on chromosome 20
SCID (severe combined immunodeficiency disease) aka “bubble-boy” disease
this is an enzyme needed for converting adenosine to inosine. a deficiency of this enzyme causes SCID.
adenosine deaminase (ADA)
this medication is used to treat ADA deficiency. it was the first enzyme replacement therapy. it is a PEG enhanced version of the ADA enzyme (injections of ADA need to be modified in order to be effective - attaching PEG increases its circulating life and masks the bovine-derived ADA to avoid immunogenic reactions)
Adagen
this disease is caused by inborn errors of metabolism characterized by the accumulation of substrates in excess in various organs’ cells due to the defective functioning of lysosomes. examples:
- Fabry disease
- Gaucher disease
- Niewmann-Pick C disease
- Tay-Sachs disease
lysosomal storage diseases
this is an inherited metabolic disease caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAG)
- it is the absence or dtysfunctioning of any of the 11 enzymes required to break down GAGs
- seven distinct clinical types (I-VII)
mucopolysaccharidosis
these are long chain carbohydrates that help build bone, cartilage, tendons, corneas, skin and connective tissue. are also found in the fluid at joints as lubricants
GAG
accumulation of ____ in the cells, blood and connective tissues can cause permanent, progressive cellular damage that affects the individuals appearance, physical abilities, organ and system functions and in most cases mental development
GAGs
this is a distinct clinical type of mucopolysaccharide, that has three subtypes based on the severity of symptoms. all three types result from an absence of or insufficient levels of the enzyme alpha-L-iduronidase (IDUA)
MPS I
this subtype of MPS I is also called Hurler syndrome or alpha-L-iduronidase deficiency and is the most severe subtype. features include progressive deterioration, enlarged liver, spleen and heart, dwarfism, gargoyle like faces, progressive mental retardation, restricted joint movement, death occurring by age 10
MPS I H
this subtype of MPS I is also called Scheie syndrome and is the mildest subtype
MPS I S
this subtype of MPS I is also called Hunter-Scheie syndrome, less severe than Hurler syndrome
MPS I H-S
this is used to treat alpha-L-iduronidase deficiency
Laronidase
this is responsible for the breakdown of glycosaminoglycans (GAGs). when there is a deficiency in this enzyme, it leads to GAG accumulation which results in damages in tissues and organs such as the case of MPS I
alpha-L-iduronidase
this medication has been used for MPS I since April 2003. naturally occurring enzyme alpha-L-iduronidase produced by recombinant DNA in a Chinese hamster ovary cell line. is a glycoprotein.
Laronidase-rch (Orphan Drug) - ALDURAZYME
these are pharmaceuticals used to treat rare medical conditions
orphan drugs
what are some examples of orphan disease
- cystic fibrosis
- homozygous familiar hypercholesterolemia
- Wilson’s disease
does joint restriction increase or decrease with the treatment of Aldurazyme
decrease!
this enzyme hydrolyzes glycolipid glucocerebroside to glucose and ceramide. absence of this enzyme causes Gaucher disease and as a result, cells fill up with the undigested fat which are then referred to as Gaucher cells
beta-Glucocerebrosidase
this disease is caused by a deficiency of beta-glucocerebrosidase which causes an accumulation of glucocerebroside in tissue macrophages in the liver, spleen and bone.
secondary hematologic sequelae:
- severe anemia
- thrombocytopenia
causes hepatosplenomegaly (increase size of liver and spleen)
skeletal complications include: bone pain, osteonecrosis, osteopenia
Gaucher disease
this drug is a variant of beta-glucocerebrosidase. produced by recombinant DNA technology using Chinese hamster ovary. the oligosaccharide chains at the glycosylation sites have been modified to terminate in mannose sugars. these mannose-terminated oligosaccharide chains of imiglucerase are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher cells
Cerezyme (imiglucerase for injection)
when is Cerezyme used
for long-term enzyme replacement therapy for patients with type I Gaucher disease with one or more of the following conditions
a) anemia
b) thrombocytopenia
c) bone disease
d) hepatomegaly or splenomegaly
this enzyme hydrolyzes lipids. a deficiency in this enzyme can cause complications such as:
liver-enlarged liver, fibrosis, cirrhosis, liver failure
CVS: low HDL, high LDL, heart attack and stroke
spleen: enlarged spleen, low platelet count leading to bleeding problems
GI: pain, bleeding, diarrhea, poor absorption of nutrients leading to malnutrition and poor growth
LAL (lysosomal acid lipase)
how can LAL (lysosomal acid lipase) be treated?
- low fat diets
- lipid lowering medications
- stem cell transplant
- liver transplant
- I.V. infusion of sebelipase alpha, Kanuma
what can be used to treat defective lysosomal enzyme for the treatment of lysosomal storage diseases
- gene therapy
- enzyme replacement therapy
- enzyme enhancement therapy
