Bio 6 Flashcards
What can gene therapy be used for?
Gene repair Pro-drug metabolising enzyme therapy to sensitize cancer cells Viral oncolysis Modification of tumour microenvironment Drug resistance therapy Immunotherapy
What are the commerical barriers to gene therapy?
Costs are high for materials
Small market of suitable patients
Costs of patents and licences
Biological barriers to gene therapy
Many genes may be mutated
Variation within tumour
Variation between patients
Require majority of cancer cells to be affected
What are microRNAs?
short RNA molecules that bind to mRNA targets and repress gene expression
Oncomirs
Repress TS genes
Tumour suppressor miRs
Repress oncogenes
How can microRNAs be exploited for cancer therapies?
Block oncomirs: increase tumour suppressor genes
Increase tumour suppressor microRNAs: downregulate oncogenes
Anti-miRs (antagomirs)?
Inactive oncomirs, bind and sequesters
Oligonucleotides complementary to miRs
MicroRNA sponges?
Mop up oncomirs
They have multiple decoy binding sites for miR
RNA sequence is complementary to multiple target miRs
MicroRNA mask?
Block oncomirs
Oligonucleotide complementary to target mRNA
Binds to mRNA to block access to miRs
Upregulate tumour suppressor miRs?
Oligonucleotide to mimic TS miRs
Replacement therapy
What are the barriers to miR therapies?
- Stability: oligonucleotides only last a few minutes in blood stream; chemical modification into liposomes can increase increase half-life
- Excretion: modications to increase albumin binding, slows renal clearance
- Cellular uptake and targeting: large size and polar make it difficult to get across membranes, therefore use carrier- active uptake
What are the biologial issues with miR therapies?
High dose is required
Transient inhibition; repeated doses needed
Off-target effects; multiple targets for each miRs
Pro-drug metabolising enzyme therapy example and how it works?
Herpes Simplex TK
Phosphorylates prodrugs such as valaciclovir to toxic nucleotides
Uses gamma retroviral vector or cancer cell surface antigen to target cells
Not licenced
Viral oncolysis example
Adenovirus dl1520; uses defective p53 pathway
Only replicates in cancer cells