Introduction to Pharmacogenetics Flashcards
What is a genome?
A genome is an organism’s complete set of genetic instructions.
What is diagnostic odyssey?
A diagnostic odyssey is defined asthe time between when a symptom or feature of a genetic or rare disease is noted to the time when a final diagnosis is made.
What is the difference between germline and somatic mutations?
Germline mutations are changes to your DNA that you inherit from the egg and sperm cells during conception.
Somatic mutations are changes to your DNA that happen after conception to cells other than the egg and sperm
How can germline and somatic mutations associated with cancer be identified?
Germline (hereditary) mutations are identified by comparing genomes of people with cancer vs people without
- e.g. BRCA1 and breast cancer
Somatic mutations are identified by comparing genome from cancer cells vs non-cancer cells in the same patient
What are gene therapies?
uses new technology to deliver tailor-made genetic material (DNA) into a patient’s cells to treat disease
- modifies a person’s genes to treat or cure disease
How can gene therapies work?
DNA is artificially inserted into a cell to treat genetic disease
- alters protein production in cells that do not produce a protein when they should or produce altered versions that does not function properly
delivers a functional copy of a gene to cells
- uses a non-infectious viral carrier
- does not alter the patient’s genome
- exists as free floating DNA in the nucleus where it can be transcribed into mRNA
is most practical for diseases affecting a single organ as therapy can be targeted
What is Zolgensma?
a treatment for spinal muscular atrophy
- a neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting.
delivers a virus packaged working copy of the SMN1 gene into patients cells
- SMN1 gene codes for proteins required for nerve cell function
is a curative single dose treatment
What are the benefits of gene therapy in cancer treatment?
compared to traditional cytotoxic cancer therapies
- targets only cancer cells with the mutation
- has better outcomes and survival rates
- fewer severe adverse effects
allows for stratification (sorting) of cancer based on specific genetic causes
- tumour agnostic = treatment for any cancer based on specific gene presence rather than where the cancer started
- mutational signatures
What is cystic fibrosis? How does it work?
cystic fibrosis occurs when there is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR)
- results in defective CFTR function as a chloride ion channel leading to dehydration of secretions (excessive mucus)
- results in excessive loss of salt in sweat due to excessive sodium reabsorption (typically inhibited by CFTR)
How has gene therapy been used to treat cystic fibrosis?
new targeted treatments target the specific molecular defects caused by mutations
- CFTR modulators are classified into 4 groups = correctors, potentiators, stabilisers and amplifiers
correctors - help the CFTR protein to form the right 3-D shape so that it is able to traffic to the cell surface (C2)
potentiators - CFTR modulators that hold the gate open so chloride can flow through the cell membrane (C3)
What are the classes of cystic fibrosis mutation?
Class 1 - protein production mutation (no mRNA so no CFTR)
Class 2 - protein processing mutations (no trafficking of CFTR to the plasma membrane due to incorrect folding)
Class 3 - gating mutation (gate is permanently closed so no Cl movement)
Class 4 - conduction mutations (decreased conductance of Cl due to irregular gate shape)
Class 5 - insufficient protein mutation (reduced amount of CFTR at the plasma membrane)
Class 6 - unstable protein mutation
How can gene therapy be used to treat hypercholesterolaemia?
Familial hypercholesterolaemia is an inherited condition that causes high cholesterol levels from birth and a significantly increased risk of early heart disease
Caused by single highly penetrant mutations in LDLR, APOB, PCSK9 or APOE genes
- can be diagnosed and early, aggressive treatment can be started to prevent CVD
How can gene therapy be used to predict drug resistance?
Sequencing the genome of infective organisms can identify resistant strains and guide treatment options
Tuberculosis – to identify different strains that are resistant to some antimicrobial treatments
What is pharmacogenetics? Why is it studied?
the study of genetic causes of individual variations in drug response
genetic variants in an individual can be used to predict the likelihood that a drug will be effective, or cause unintended harm through an adverse reaction
How are pharmacogenetics and ADRs related?
abacavir
fluoropyrimidines (5-FU, capecitabine)
abacavir
- people have severe hypersensitivity reactions due to the presence of HLA allele HLA-b*57:01 being a predisposing factor
fluoropyrimidines
- people can develop toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency as DPD metabolises it into its inactive form
