L30 - New & Emerging Drug Technologies Flashcards
What does a mutation in DNA result in?
Defective protein requires for normal cell function
= causes disease
What are some diseases are exacerbated by?
Increased levels of particular proteins
What can sub-physiological levels of protein be overcome by?
Delivering exogenous protein
What can nucleic acids be used as?
Treatment in all scenearios
What does therapeutic protein overcome?
Difficulties of producing & purifying recombinant proteins
- getting patient’s cells to do it
- transicent - repeated injections of gene/vector requires
What is siRNA? What does it do?
Small interfering NRA
- knocks down gene expression if sequence is known
What are advantages of siRNA?
- readily designed
- readily synthesised
What is miRNA? What is it derived from?
Micro RNA
- genes that specifically code miRNAs (not proteins
What are miRNA important in?
Regulating gene expression (1/3 of genes)
What are advantages of miRNA?
- dont cause mRNA destructions (repress or destabilise)
- strong evidence of involvement in diseases states (inc. cancer)
What can be delivered to cells to replace missing miRNAs?
DNA coding underexpressed or missing miRNAs
What can overexpressed miRNAs be inhibited by?
Anti-miRNAs
- complementary nucleotides that bind to the problem miRNA
What are RNA vaccines?
- viral mRNA absorbed by cells
- expressed on surface
- labelled as foreign cells
What is cell therapy?
Delivery of cells to the patient to correct disease or damge
- may be combined with genetic strategies (secrete therapeutic protein, reprogramming immune cells)
What is strimvelis? What does it treat?
First ex vivo stem cell gene therapy
- treats severe combined immunodeficiency cause by adenosine deaminase deficiency
- autologoes CD34+ cells expressing functional ADA
- (rare)
How are cell therapies with CAR T cells done?
- remove blood from patient (get T cells)
- make CAR T cells in lab
- grow millions
- infuse CAR T cells into patient
- CAR T cells bind to cancer cells, killing them
What are approved CAR T cell therapies?
- kymriah
- yescarta
- tecartus
- breyanzi
- ABECMA
- carvykti
What are emerging cell therapies?
- TCR-T cells
- CAR-M
- CAR-NK cells
How do CAR T cells work?
- recognise antigen on tumour cell
- causes transcription of T cell effector function
= perforin and granzyme release
What was combination cell-gene therapy?
- trialed in 56 patients
- mesenchymal stem cells transfected with gene (TRAIL)
- off the shelf treatment
- scaling up cell culture (key)
- funded through the biomedical catalyst (MRC and Innovate UK)
What are current approaches to nucleic acid therapy like?
Often transient
- varying degrees of success
What is gene editing?
Permanently editing the genome to correct a defect, knocking down a specific gene/activating a gene
What are ways of gene editing?
Break in double strand break
- gene disruption
- gene correction
- gene insertion
What is an example of gene editing? What does it do?
CRISPR/Cas9 (system from bacteria can be used to edit DNA)
- modifies genes in human cells in vitro and in vivo
- used to inactivate, correct and insert genes
How could gene editing cure HIV?
Cause mutation in CCR5 expression
- prevents HIV from entering cells as not expressed on T cells
What are examples of stem cell therapies?
- totipotent
- pluripotent
- multipotent
What is stem cell therapy to cure blindness?
Limbal stem cell transplantation
- cure blindness due to corneal burning
What does tissue engineering aim to do?
replace diseased or damaged livgin tissue with living tissue designed and contructed for the needs of each individual
What are the steps in tissue engineering?
- isolate cells
- expand cell number
- seed on suitable scaffold
- culture under suitable conditions to generate a mature tissue
- implant tissue in patient
What is a way of tissue engineering for implants?
3D bioprinting
What is controlled drug delivery used for?
- long term treatment (entrap drug in polymer matrix, dif shapes and szes)
- small quantites released over a long period
What are way of controlled drug delivery?
- polymer degrades over time, releasing drugs
- polymer doesnt degrade, drug slowly diffues
(Microchips)
Why would controlled drug delivery be favoured?
- sustained therapeutic plasma conc
- improved compliance - patient can’t forget dose
What does targeted drug delivery aim to do?
- accumulate and retain drug at site of action
- minimise loss in transit
- protect drug from premature clearance
- aid intracellular delivery (in necessary)
What are antibody-drug conjugates (ADCs)?
mAb therapy
- need to be combined with small drug chemotherapy/radiotherapy
- binds to specific targets, can deliver highly toxic drugs to site of action
What are ADCs being developed for?
Delivery of chemotherapeutics to cancerous cells
What are the current ADCs like on the market?
2 on the market, many nearing approval
- multiple drug molecules attaches via cleavable linker
What is the Kadcyla ADC?
Combination os trastuzamab and cytotoxic drug
- increase median overall survival in HER2+ metastatic breast cancer by almost 6 months
What are oncolytic viruses?
Viruses that break apart cancerous cells
- infect cancerous cells and cause lysis and apoptosis
What does the enhanced permeability and retention have an effect on (EPR)?
- blood vessels in tumours are leaky
- macromolecules and nanoparticles easily enter, poorly drained
- accumulation in tumours is possible
How could you use bacteria to fight cancer?
- oxygen deficient (hypoxic) areas, resistant to chemo/radiotherapy
- some are olbigate anaerobes, can colonise hypoxic areas
What is an examples of a bacteria that could fight cancer?
Probiotic-guided CAR (ProCAR)-T cells
