Genetic treatments Flashcards
What are inborn errors of metabolism?
Rare inherited disorders whereby the body is unable to effectively convert substrate into energy or for the synthesis of ATP (Glycolysis, and beta oxidation)
Disorders attributed to defects in specific enzymes responsible for the hydrolytic degradation (metabolism) of food
What inheritance pattern is demonstrated by phenylketonuria (PKU)?
Autosomal recessive
Which metabolism is affected by PKU?
Phenylalanine metabolism
Why is phenylalanine metabolism affected by PKU?
There is a deficiency in the enzyme phenylalanine hydroxylase (PAH)
The enzyme catalyzes the amino conversion of phenylalanine into tyrosine
Leads to an accumulation of phenylalanine and its metabolites in tissues and bodily fluids
What is the PAH gene mutation in terms of chromosomes?
12q23.2
Explain the pathophysiology of PKU in terms of phenylalanine accumulation?
Elevated levels of Phe, leads to increased production of phenyl ketones, these compounds express degrees of neurotoxicity.
Phe affects the synthesis of inhibitory monoamine neurotransmitters (Responsible for physiological and homeostatic processes)
What are the symptoms associated with untreated PKU?
Major cognitive impairments; behavioural difficulties; fairer skin tone, hair and eyes; lack of melanin and recurrent vomiting.
How is PKU treated?
Patients are given a low protein diet (protein diets have high Phe content) - in a combination of Tyrosine supplements
Screening program introduced to measure levels of phenylalanine upon initial recognition of disease; treatment succeeds in scientific understanding.
What is neutral amino-acid therapy?
Supplement partially inhibits the absorption of phenylalanine
What is the inheritance pattern of hemophilia?
Sex-linked inherited genetic condition
What is hemophilia?
Sex-linked genetic conditions which impair the body’s ability to release clotting factors in aim to produce blood clots.
Symptomatically, this increases the clotting time after injury, contributes to easy bruising and increased riskof internal bleeding (brain and joints)
The condition typically caused by hereditary lack of coagulation factor VIII,
Heat treatment of product kills HIV & HBV
What treatments are available for hemophilia (5)?
Cryoprecipitate Desmopressin Clotting preserving medications Fibrin sealants Replacement therapy
How can cryoprecipitate be used to treat hemophilia?
Prepared from plasma & purified, contains factor VIII, and platelet concentrates can be intravenously administered as a replacement therapy
Recombinant clotting factor VIII gene cloned to synthesize an increased level of factor can be used.
How can desmopressin be used to treat hemophilia?
Hormone can stimulate the release of more clotting factors, administered intravenously or as a nasal spray, only for milder variants of hemophilia.
How do clotting preserving medications work?
Medications inhibit and reduce fibrinolysis - reducing clot degradation
How do fibrin sealants work?
Medications can be applied directly to the wound sites to promote clotting & bleeding
Which recombinant protein is injected in patients with Fabry & Pompe diseases?
Alpha galactosidase A
What is the first phase of drug development?
Drug development relies on multiple phases to ensure efficacy
First stage discovery is based on preclinical understanding (lab-based experimental procedures to provide evidence to back hypothesis)
Animal testing to evaluate toxicity, and clinical testing to identify dosages
How many main phases are there for clinical drug testing?
Phase 1-3
3 phases
What is phase 1 for clinical testing?
Safety in healthy volunteers (<100)
What is phase II during clinical testing?
Check therapeutic effect (100-300)
What is phase III of clinical testing?
Large scale therapeutic trials (200-3000) Approval: EMA & FDA
How are NHS drugs approved?
Prescription of NHS drugs require approval by the National Institute for Health & Care Excellence (NICE) for England & Wales.
Healthcare improvement in Scotland
How are NHS drugs approved?
Depending on cost-effectiveness and efficacy
Provides guidelines for treating conditions
What are pharmacological chaperones?
Protein folding and processing occurs in the endoplasmic reticulum (ER), where the protein tertiary structure is maintained and constructed to confer specificity.
Chaperone proteins regulate the folding process. Implemented system in ER degrades misfolded proteins (subject degradation pathway)
How do molecular chaperones work?
Molecular chaperones in the endoplasmic reticulum are designated to support nascent proteins entering the ER lumen and assist towards attaining the correct protein conformation and prevent non-specific aggregation
Mutations can alter the polypeptide sequence, transforming the trinucleotide sequence of a codon, encoding for a different amino acid (impacting the stereochemical and polar properties of the chain) - attributing to altered bonds.
Which enzyme is misfolded in Fabry disease?
alpha-Galactosidase A
Which substrate accumulates within blood vessels, tissue, and organs as a result of Fabry disease?
Globotriosylceramide
Which molecular chaperone is used in Fabry disease?
Migalastat
How does Migalastat stabilize and treat Fabry disease
Chaperone stabilizes enzyme by binding to active site to mutant forms of alpha-galactosidase A; conforming for correct structural configuration within the endoplasmic reticulum, and facilitating normal trafficking to lysosomes. Migalablast antagonist of substrate - mutation-specific
When was migalastat approved by NICE?
Feb 2017
What are pharmacological modulators?
Are receptor agonists/antagonists behaving through ion channel activation/inhibition
What is the function of the BCL-ABL kinase inhibitor?
Product of Philadelphia chromsome, drug only binds to mutant kinase form
How does the pharmacological modulator, ivacaftor treat cystic fibrosis?
CFTR protein defection causes a dysfunctional chloride ion channel. Mutations (33) attributed to channel closure
ANSWER: Facilitates increased chloride transport by potentiating the channel open probability if the G55ID-CFTR protein. Drug is mutation-specific
How can combination therapy be used to treat cystic fibrosis?
Orkambi involves a combination of chaperone and activator molecules
Lumacaftor and ivacaftor respectively.
Refolded protein channel does not exhibit complete activity
Which cystic fibrosis mutation causes chloride channel dysfunction?
f508del