Treatment of Genetic Disorders

Question 1

describe an example of coenzyme supplementation

Answer 1

• increasing vit. B6/PLP in patients with homocystinuria to increase the activity of the mutant cystathione B-synthase

Question 2

describe PKU I vs PKU II and treatment for PKU-I

Answer 2

• PKU I = Phe hydroxylase deficiency
  
  • dietary restriction of Phe and supplementation w/ tyrosine
  • pharmacological doses of BH4 (sapropterin)
• PKU II: lack of BH4/BH2
  
  • prognosis much worse since BH4 needed in brain for catecholamine synthesis

Question 3

describe treatment in urea cycle disorders

Answer 3

• metabolite diversion
  
  • ammonia cannot be removed by the urea cycle because of a genetic defect in urea cycle enzymes
  • the administration of sodium benzoate diverts ammonia to glycine synthesis which is eventually excreted as hippurate

Question 4

describe a solution of protein stability in protein replacement therapies

Answer 4

• polyethylene glycol derivatization (PEGylation): carbohydrate moiety is added to protein to shield it but does not interfere with enzyme active site
  
  • may protect protein from rapid degradation
  • may reduce clearance by kidney
  • may reduce immune response

Question 5

describe a treatment of AR-SCID (ADA deficiency)

Answer 5

• bone marrow transplant
• protein replacement therapy
  
  • PEG-ADA was found to be better than unmodified ADA in restoring immune function
• gene therapy

Question 6

explain how Gaucer disease may be treated with enzyme replacement therapy

Answer 6

• PEGylation of recombinant B-glucocosidase (aka B-glucocerebrosidase) protein
  
  • may be targeted to macrophage lysosomes
  • exposure of mannose residues allows lysosomal uptake

Question 7

name 2 examples therapeutic targeting of signal transduction pathways in cancer cells

Answer 7

• tyrosine kinase inhibitor: imatinib aka Gleevac
• HER2 antibodies: Herceptin used in Her2+ breast cancer

Question 8

explain epigenetic modification used in sickle cell disease

Answer 8

• switching on fetal globin synthesis by using hydroxyurea by inhibiting histone deacetylation

Question 9

describe how adenoviruses work

Answer 9

• adenovirus contains the engineered functional gene that is then injected into the cell
  
  • the gene is then extra-chromosomal (NOT part of cell’s genome)

Question 10

explain 2 problems with gene therapy

Answer 10

1. immune response
2. tumor formation
   
   • insertional mutagenesis induces a tumor if the DNA is integrated in the wrong place in the genome
     
     • may destroy a tumor suppressor gene
     • may activate a protooncogene

Question 11

describe Gendicine

Answer 11

• Gendicine uses an adenovirus as a vector for p53
  
  • virus is injected directly into the tumor, reinstating endogenous production of p53