Lecture 24: Treatments Of Genetic Disease Flashcards
What is the largest group of genetic diseases?
Inborn errors of metabolism, affect variety of pathways:
- carbohydrate
- fatty acid
- proteins
Lack of enzyme stops production of certain product which can lead to build up of toxic alternate products
How were genetic diseases primarily treated?
By controlling diet or replacing what has been lost
What are the 3 stages of drug development?
1) Drug discovery
2) Pre-clinical development
3) Clinical development (safe in humans –> therapeutic effect in few patients –> large scale therapeutic trials)
Which organisation gives approval for drugs to be prescribed by the NHS?
NICE (national institute for health and care excellence)
What do therapies targeting proteins try to do?
Try to normalise function of mutant protein
What are pharmacological chaperones?
a drug that acts as a protein chaperone. That is, it contains small molecules that enter cells and serve as a molecular scaffolding in order to cause otherwise-misfolded mutant proteins to fold and route correctly within the cell.
What are pharmacological modulators?
- receptor agonists/antagonists
- ion channel activators/blockers
How can diseases caused by non-sense mutations that result in a premature stop codon be treated?
Using drugs that can read through specific non-sense mutations to produce some sort of functional protein e.g. turning Duchenne muscular dystrophy into Becker muscular dystrophy
What is the concept of gene therapy?
Recessive disease - replace defective gene
Dominant disease - delete defective gene
Why is gene therapy difficult to achieve in practice?
- achieving specificity
- getting therapy to right place
- maintain expression
Is gene therapy easier to achieve in vitro or in vivo?
In vitro
What is mitochondrially inherited disease therapy?
IVF treatment that takes DNA from fertilised patient egg and transfer to donor egg with normal mitochondria
Outline virus gene therapy.
can engineer virus to carry therapeutic gene
- virus acts as vector and binds to cell membrane
- vector packaged in vesicle
- vesicle breaks down releasing vector
- vector/virus injects new gene into nucleus
- cell makes protein using new gene
What is Chimeric Antigen Receptors Cell Therapy (CAR-T)?
type of immunotherapy which involves collecting and using the patients’ own immune cells to treat their condition - used to treat cancer
- T-cell receptor antigen bound to MHC
- low affinity
- CAR recognise antigen directly
- variable region monoclonal antibody scFv - recognise cancer cell
- T cell receptor and co-receptor signalling domain work together to kill cancer cells
CAR T cells are able to bind to an antigen on the cancer cells and kill them
Outline how in vivo therapy supplement works.
- useful if patient lacks functional gene
- use virus to carry in working copy
- can inject systemically or locally
What are antisense oligonucleotides?
short, single-stranded DNA molecules that interact with messenger RNA to prevent translation of a targeted gene. Their DNA sequence is complementary to the specific mRNA target; binding leads to degradation of the DNA sequences with failure of protein production
Outline how in vivo therapy knockdown therapy works.
- useful for disease caused by gain of function
- currently no successful therapies
- principle works using oligonucleotides
- mutation specific
How can exon skipping treat genetic diseases?
- oligonucleotides cause disease-causing exon to be skipped
- puts RNA back in reading-frame
- generally only for large proteins
- useful in limited circumstances
What are some possible future therapies?
- gene cell therapy
- gene-editing using CRISPR-Cas9
What is CRISPR-Cas9?
- Bacterial ‘immune system’ that can disable bacteriophages
- Cas9 is endonuclease
- CRISPR derived from previous bacteriophage
- recognises and cleaves DNA CRISPR hybrids
What can CRISPR-Cas9 do?
- gene editing to correct relatively small errors –> point mutations
- cannot correct large changes
- may have off target effects, not currently used in humans
- same problem as other methods, targeting, getting into cell
