Bio 6 Flashcards
(33 cards)
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
How does targeting the tumour microenvironment as a therapy work?
Prevents angiogenesis by modifying normal cells
Doesn’t require high efficiency of transduction
Modify immune response and metastatic potential?
Cancer cells don’t exist in isolation
What doesnt require such high energy transduction?
When you target the host, not the cancer
How can gene therapy reduce toxicity?
By increasing the therapeutic index
What is the recent progress for ALL (acute lymphoblastic leukemia)?
donor T-cells from healthy volunteer, genetically modified to attack CD19+ cells and resistant to immunotherapy which would otherwise kill all T-cells
this is transplanted into patient and immune system kills all cancer cells and also donor T-cells and so is free from genetic modification as well as cance
What are monoclonal antibodies?
proteins produced by the immune system to bind specifically to foreign antigens
produced by B lymphocytes
come from single clone of B lymphocytes and target a single epitope
Polyclonal antibodies
come from many clones of B lymphocytes
target multiple epitopes
Draw structure of antibody (immunoglobulin)
Antigen binding site
Variable and constant regions
Light chain and heavy chain
Disulphide bonfs
What are MAbs used for?
Make cells visable to immune system: mark
Stop cells dividing: against growth receptors
Target therapies: conjugated to enzyme
Diagnosis: hormone receptors
What is rituximab?
targets CD20 on B cells and kills them in lymphomas and leukemias.
- causes antibody dependent cell mediated cytotoxicity
- causes complement mediated cytotoxicity
