Genetics Quiz 4

Gene replacement therapy

Re-introduction of the normal version of the mutated gene that is not expressed to correct a genetic condition

Potential problem every time DNA is introduced into cells

Insertional mutagenesis

SCID treatment

Strimvelis which is a gene therapy medication to remove hematopoietic stem cells and transducer with a virus expression wild type genes

Lebel Congential Amaurosis

Type of retinal dystrophy caused by a mutation in RPE65

Treatment of Lebel congenital Amaurosis

Luxturna which is a gene therapy introducing the wild type RPE65 gene through intraocular injection

Treatment for sickle cell disease

Ex vivo modification of stem cells such as retroviral transduction of bone marrow stem cells cells with wild type HBB gene

CRIPSR/Cas9 gene inactivation of BCL11A which is responsible for inactivation of HBF

Anti-sense therapy

Design of a DNA oligonucleotide for target mRNSA to block translation

Problem with viral delivery

Insertional mutagenesis and loss of transgene overtime

RNA interference

Design of an RNA oligonucleotide that searches and degrades the target mRNA

CRISPR gene inactivation

Cas9/sgRNA complex binds to specific site to generate DSB that will be repaired by NHEJ with a deletion

CRIPSR gene editing

Cas9/sgRNA complex binds to specific site and generates DS and is repaired with HR that introduces a template of the corrected sequence

Problem with gene editing

Not enough accuracy or precision, hard to induce HR and not NHEJ

Problem of CRISPR

No way to turn off Cas9 and no way to Ryle out off-targett effects

Techniques used by genetic testing

Genotyping array (known SNP), exome sequencing (sequences all exons in a sample), and whole genome sequencing (all DNA in a sample)

Decreased activity of CYP450 enzymes

Slow metabolism → build up of drug → DECREASE DOSE → risk of adverse effects

Increased activity of CYP450 enzymes

Fast metabolism → INCREASE DOSE → risk of decreased drug efficacy

Patient with CYP2C9 polymorphism

Slow metabolism of warfarin → Need low dose → risk of uncontrolled bleeding

Decreased activity of prodrug enzyme

decreased metabolism of drugs → INCREASE DOSE

Increased activity of prodrug enzyme

Increased metabolism of drugs → DECREASE DOSE → risk of adverse effects

CYP2D6 polymorphism

Prodrug for codeine to morphine

Ultrarapid metabolizers need to lower dose and they are at risk of analgesic effects and toxic effects

Slow metabolizers are at risk of reduced analgesic effects

Polymorphism in VKORC1 amino acid sequence - Warfarin resistance

Leads to decreased drug activity and decreased anticoagulant effect → patient needs alternative drug

Polymorphism decrease in VKORC1 - warfarin sensitivity

Increased anticoagulant levels → Patient need a lower dose

Polymorphism in Simvastin/SLCO1B1

Causes defects in drug transporters inside the cell causing decreased activity and drug build up causing myopathy

What is most associated with type B adverse drug reactions

HLA polymorphisms

Allopurinol adverse reaction

Hypersensitivity reaction leading to SCAR (potentially life threatening)

Abacavir adverse reaction

Reverse transcriptase inhibitor for HIV that can lead to hypersensitivity reaction and DRESS which is systemic and life threatening

DNA microarray test

Looks for all SNPs, including unknowns and rare variants → positive test is yellow