4. clinical applications of biopharmaceuticals - Enzymes

Question 1

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

Answer 1

SCID (severe combined immunodeficiency disease) aka “bubble-boy” disease

Question 2

this is an enzyme needed for converting adenosine to inosine. a deficiency of this enzyme causes SCID.

Answer 2

adenosine deaminase (ADA)

Question 3

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)

Answer 3

Adagen

Question 4

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

Answer 4

lysosomal storage diseases

Question 5

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)

Answer 5

mucopolysaccharidosis

Question 6

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

Answer 6

GAG

Question 7

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

Answer 7

GAGs

Question 8

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)

Answer 8

MPS I

Question 9

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

Answer 9

MPS I H

Question 10

this subtype of MPS I is also called Scheie syndrome and is the mildest subtype

Answer 10

MPS I S

Question 11

this subtype of MPS I is also called Hunter-Scheie syndrome, less severe than Hurler syndrome

Answer 11

MPS I H-S

Question 12

this is used to treat alpha-L-iduronidase deficiency

Answer 12

Laronidase

Question 13

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

Answer 13

alpha-L-iduronidase

Question 14

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.

Answer 14

Laronidase-rch (Orphan Drug) - ALDURAZYME

Question 15

these are pharmaceuticals used to treat rare medical conditions

Answer 15

orphan drugs

Question 16

what are some examples of orphan disease

Answer 16

• cystic fibrosis
• homozygous familiar hypercholesterolemia
• Wilson’s disease

Question 17

does joint restriction increase or decrease with the treatment of Aldurazyme

Answer 17

decrease!

Question 18

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

Answer 18

beta-Glucocerebrosidase

Question 19

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

Answer 19

Gaucher disease

Question 20

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

Answer 20

Cerezyme (imiglucerase for injection)

Question 21

when is Cerezyme used

Answer 21

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

Question 22

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

Answer 22

LAL (lysosomal acid lipase)

Question 23

how can LAL (lysosomal acid lipase) be treated?

Answer 23

• low fat diets
• lipid lowering medications
• stem cell transplant
• liver transplant
• I.V. infusion of sebelipase alpha, Kanuma

Question 24

what can be used to treat defective lysosomal enzyme for the treatment of lysosomal storage diseases

Answer 24

• gene therapy
• enzyme replacement therapy
• enzyme enhancement therapy

Question 25

what can be used to treat accumulated substance in lysosomal storage diseases

Answer 25

• surgical procedures (e.g. splenectomy)
• substrate reduction therapy

Question 26

what can be used to treat secondary effects for the treatment in lysosomal storage diseases

Answer 26

treatment of kidney, liver and neurological complications with available medicines and surgical procedures

Question 27

what are the two strategies for enzyme cancer therapy

Answer 27

• cell division based therapy
• cell communication based therapy

Question 28

what is the problem with enzyme cancer therapy

Answer 28

toxicity due to limited selectivity

Question 29

this enzyme is used to treat leukemia. has little toxicity. it hydrolyzes asparagine which depletes blood asparagine which starves the fast dividing leukemia cells

Answer 29

L-asparaginase

Question 30

if L-asparaginase would result in the depletion of asparagine, would it also starve other cells causing toxicities?

Answer 30

no. most cells make their own asparagine using asparagine synthetase

Question 31

this is made from bacteria source and is the pegylation of L-asparaginase. used for acute lymphoblastic leukemia; also used in other leukemias and non-Hodgkins lymphoma. should be administered no more frequently then q 14 days. should not be administered if it was frozen, left at room temp for more than 48 hours or shaken vigourosly

Answer 31

PEG-L-asparaginase

Question 32

this is an enzyme that can be used to alleviate patient symptoms due to disease or medical treatments; is found from bacteria to mammals but is absent in humans. can be used to break down uric acid.

Answer 32

urate oxidase

Question 33

this medication is a recombinant rate oxidase produced by a genetically modified Saccharomyces cerevisiae strain. the cDNA coding for irate oxidase was cloned form a strain of Aspergillus flavus. a tetrameric protein. the drug is a sterile, white to off white lyophilized powder intended for intravenous administration after reconstitution. indicated for management of plasma uric acid levels in paediatric patients with leukemia, lymphoma and solid tumour malignancies who are receiving anti-cancer tx expected to result in a tumour lysis and subsequent elevation of plasma uric acid. may also be sued in those with chronic hyperuricemia in patients with “treatment failure gout”

Answer 33

ELITEK (rasburicase)

Question 34

this is an inherited chronic disease that affects the lungs and digestive systems of children and adults. a defective gene causes the body to produce unusually thick sticky mucus that:
- clogs the lungs and leads to life-threatening lung infections
- obstructs the pancreas and stops natural enzymes from helping the body break down DNA and absorb food
symptoms include: very salty tasting skin, persistent coughing, frequent lung infections, wheezing or SOB, poor growth/weight in spite of a good appetite, greasy bulky stools

Answer 34

cystic fibrosis

Question 35

in cystic fibrosis, mutations cause formation of abnormal ____________ which is a membrane spanning glycoprotein. dysfunction of this produces dehydrated airway secretions with abnormal clearance properties (very thick mucus containing large quantities of DNA)

Answer 35

cystic fibrosis transmembrane conductance regulator (CFTR)

Question 36

this is a recombinant human deoxyribonuclease I. it is administered by inhalation of an aerosol mist produced by a compressed air driven nebulizer system. it is used in the management of advanced CF as it breaks down excessive amounts of DNA present in CF patients which in turn alleviates obstructive pulmonary difficulties and decreases infections and inflammation

Answer 36

pulmozyme

Question 37

what can be used for management in CF pts

Answer 37

• preventative antibiotic therapy
• anti-inflammation
• hydration agents
• pulmozyme
• CFTR modulators (a few new agents at diff. stages of clinical trials)