SU6

Question 1

What are the three broad approaches to treating genetic disease mentioned in the ‘Big Picture’ overview?

Answer 1

Supplementation (augmentation), counteracting harmful effects, and reducing susceptibility.

Question 2

Supplementation therapy is most effective for treating which type of genetic disorders?

Answer 2

Recessive loss-of-function disorders.

Question 3

In the context of treating genetic disease, what is the goal of therapies that ‘counteract harmful effects’?

Answer 3

To target toxic metabolites, abnormal cells (like cancer), or misfolded proteins.

Question 4

What is the therapeutic strategy for 21-Hydroxylase deficiency, an inborn error of metabolism?

Answer 4

Supplementation therapy, using hormone replacement for cortisol and aldosterone.

Question 5

How does the drug nitisinone treat Type I Tyrosinemia?

Answer 5

It blocks an upstream enzyme in the metabolic pathway, reducing the production of toxic metabolites.

Question 6

In urea cycle disorders, what is the purpose of administering sodium benzoate?

Answer 6

It shunts toxic ammonia into the glycine pathway for excretion.

Question 7

Which two levels of biological organisation are targeted by treatments for Phenylketonuria (PKU)?

Answer 7

The environmental/lifestyle level (diet) and the metabolic/biochemical level (managing metabolites).

Question 8

The field that studies how genetic variation explains why individuals respond differently to the same drug is known as _____.

Answer 8

Pharmacogenetics.

Question 9

What does pharmacokinetics (PK) describe in the context of drug response?

Answer 9

What the body does to a drug, including its absorption, distribution, metabolism, and excretion.

Question 10

What does pharmacodynamics (PD) describe in the context of drug response?

Answer 10

What a drug does to the body, including its binding to targets and its effect on biological pathways.

Question 11

Which family of liver enzymes is primarily responsible for Phase I drug metabolism?

Answer 11

The Cytochrome P450 (CYP450) family.

Question 12

What is the function of Phase II drug metabolism?

Answer 12

To add chemical groups to a drug (conjugation) to increase its solubility for easier excretion.

Question 13

In pharmacogenetics, what is the clinical outcome for a ‘poor metabolizer’ of a standard drug dose?

Answer 13

The drug accumulates in the body, potentially leading to toxicity and side effects.

Question 14

What is the clinical outcome for an ‘ultrafast metabolizer’ taking a standard dose of a prodrug like codeine?

Answer 14

Excessive activation of the prodrug, as codeine is converted to morphine too quickly, leading to potential toxicity. It could also lead to rapid clearance reducing therapeutic effect

Question 15

The dose requirement for the anticoagulant warfarin is influenced by genetic variations in which two key genes?

Answer 15

VKORC1 (the drug target) and CYP2C9 (involved in drug metabolism).

Question 16

Variation in which gene explains the different responses to the antidepressant Nortriptyline?

Answer 16

The CYP2D6 gene, which encodes a cytochrome P450 enzyme.

Question 17

Slow acetylators taking the anti-TB drug isoniazid are at higher risk of side effects due to variants in which enzyme-coding gene?

Answer 17

NAT2 (N-acetyltransferase 2).

Question 18

What is the key difference between Type A and Type B adverse drug reactions?

Answer 18

Type A reactions are predictable and dose-dependent, whereas Type B reactions are rare, not dose-related, and often have a strong genetic cause.

Question 19

Variants in the RYR1 gene predispose individuals to what rare, life-threatening reaction to certain anaesthetics?

Answer 19

Malignant hyperthermia.

Question 19

Deficiency in which enzyme, due to genetic variants, can cause life-threatening toxicity from the drug mercaptopurine?

Answer 19

Thiopurine S-methyltransferase (TPMT).

Question 20

What is the fundamental difference between somatic and germline gene therapy?

Answer 20

Somatic therapy affects only the treated individual, while germline therapy causes heritable changes passed to future generations.

Question 21

What is the primary goal of gene augmentation therapy?

Answer 21

To add a functional copy of a gene to restore a missing protein, typically for recessive disorders.

Question 22

For which types of genetic mutations is gene silencing therapy an appropriate strategy?

Answer 22

Harmful alleles, such as those causing dominant gain-of-function diseases or oncogenes.

Question 23

What is the therapeutic mechanism of Zolgensma (onasemnogene abeparvovec) for Spinal Muscular Atrophy (SMA)?

Answer 23

It is a gene augmentation therapy that uses an AAV9 vector to deliver a functional copy of the SMN1 gene.

Question 24

How does Nusinersen, an antisense oligonucleotide, treat Spinal Muscular Atrophy (SMA)?

Answer 24

It modifies the splicing of the SMN2 gene to increase the production of functional SMN protein.

Question 25

The first approved CRISPR-based therapy, Casgevy, treats sickle cell disease by editing which target?

Answer 25

It edits hematopoietic stem cells to disrupt the BCL11A enhancer, which reactivates the production of fetal haemoglobin.

Question 26

What is the mechanism of CAR-T cell therapy in treating cancers like B-cell malignancies?

Answer 26

A patient's T-cells are genetically engineered *ex vivo* to express a Chimeric Antigen Receptor (CAR) that targets cancer cells.

Question 27

Differentiate between *in vivo* and *ex vivo* gene therapy approaches.

Answer 27

In *in vivo* therapy, the genetic material is delivered directly into the patient, while in *ex vivo* therapy, cells are removed, modified in a lab, and then returned to the patient.

Question 28

What is a major advantage of retroviral and lentiviral vectors in gene therapy?

Answer 28

They integrate their genetic material into the host cell's genome, leading to long-lasting gene expression.

Question 29

What is the primary safety concern associated with integrating viral vectors like retroviruses?

Answer 29

Insertional mutagenesis, which is the risk of causing cancer by inserting the gene near an oncogene.

Question 30

Why are Adeno-associated viruses (AAVs) a popular choice for *in vivo* gene therapy, especially for eye and muscle disorders?

Answer 30

They are considered safe, elicit a low immune response, and do not typically integrate into the host genome.

Question 31

What is a significant limitation of early-generation adenoviral vectors that led to their replacement in many applications?

Answer 31

They are highly immunogenic, capable of triggering severe and even fatal immune responses in patients.

Question 32

What is a key trade-off when comparing viral and non-viral gene delivery methods?

Answer 32

Viral vectors generally have higher efficiency but greater safety concerns, whereas non-viral methods are safer but less efficient.

Question 33

What are induced pluripotent stem cells (iPSCs)?

Answer 33

Adult somatic cells that have been reprogrammed back to a pluripotent, embryonic-like state.

Question 34

What is one of the minimum requirements for gene therapy regarding the target disease?

Answer 34

The disease must have a well-defined mechanism, typically being a monogenic disorder.

Question 35

What is a major advantage of using patient-derived iPSCs in cell therapy?

Answer 35

It reduces the risk of immune rejection because the cells are genetically matched to the patient.

Question 36

For a gene therapy to be successful, what is required of the target cells or tissue?

Answer 36

The cells must be accessible to the delivery method and survive long enough for the therapy to have a durable effect.

Question 37

What is a critical requirement regarding the expression of the therapeutic gene in gene therapy?

Answer 37

The gene must produce a stable and durable effect at physiological levels, avoiding both under-expression and toxic overexpression.

Question 38

The first gene therapy for Huntington's Disease aims to reduce the toxic huntingtin protein using what molecular mechanism?

Answer 38

It uses an AAV vector to deliver RNA interference (RNAi) or a similar tool to silence the mutant HTT gene.

Question 39

What was the cause of the patient's death in the 1999 Ornithine Transcarbamoylase (OTC) deficiency trial?

Answer 39

A massive systemic immune response triggered by the high dose of the adenoviral vector used for delivery.

Question 40

What was a key lesson learned from the failure of the 1999 OTC deficiency gene therapy trial?

Answer 40

Safer vectors like AAVs and lentiviruses must be used, alongside rigorous dose-finding and immune monitoring protocols.

Question 41

Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder caused by loss-of-function mutations in which gene?

Answer 41

The SMN1 (Survival Motor Neuron 1) gene.

Question 42

Why was the AAV9 serotype specifically chosen for Zolgensma, the gene therapy for SMA?

Answer 42

Because of its ability to cross the blood-brain barrier and effectively target motor neurons.

Question 43

What remarkable outcome was observed in infants with SMA Type I who were treated with Zolgensma before symptom onset?

Answer 43

They achieved normal developmental milestones, such as sitting, standing, and even walking independently.

Question 44

In early *ex vivo* gene therapy trials for SCID, the use of retroviral vectors led to what serious adverse event in some patients?

Answer 44

Leukaemia, caused by insertional mutagenesis from the vector integrating near a proto-oncogene.

Question 45

The approved therapy Luxturna treats a form of Leber congenital amaurosis by delivering a functional copy of which gene?

Answer 45

The RPE65 gene.

Question 46

What is the mechanism of action for eteplirsen, a drug used to treat Duchenne muscular dystrophy?

Answer 46

It is an antisense oligonucleotide that promotes exon skipping to restore the reading frame of the dystrophin gene.

Question 47

The RNAi therapeutic patisiran treats transthyretin amyloidosis by silencing a gene in which organ?

Answer 47

The liver.

Question 48

In the context of CRISPR genome editing, what is the function of homologous directed repair (HDR)?

Answer 48

It allows for precise gene correction by using a supplied DNA template to repair a double-strand break.

Question 49

A clinical trial for T-cell leukaemia in 2022 marked the first use of which advanced genome editing technique?

Answer 49

Base editing.

Question 50

What is a significant safety risk associated with using pluripotent stem cells (ESCs or iPSCs) in therapy?

Answer 50

The risk of teratoma formation, which are tumours that arise from undifferentiated cells.

Question 51

What is the primary purpose of Mitochondrial Replacement Therapy (MRT)?

Answer 51

To prevent the transmission of severe mitochondrial DNA (mtDNA) disorders from a mother to her child.

Question 52

How does Mitochondrial Replacement Therapy (MRT) work?

Answer 52

The nuclear DNA from a mother's egg is transferred into a donor egg that has healthy mitochondria and has had its own nucleus removed.

Question 53

Why is Mitochondrial Replacement Therapy (MRT) considered a form of germline gene therapy?

Answer 53

Because the change is heritable, as all future descendants of the individual will inherit the donor's mitochondria.

Question 54

Besides safety concerns like immunogenicity, what is a major challenge limiting widespread access to approved gene therapies like Zolgensma?

Answer 54

Extremely high cost, often exceeding $1-2 million per patient, and the need for specialised delivery.

Question 55

Which class of drugs is comprised of recombinant proteins or antibodies, where genetic variation often affects targets or immune response?

Answer 55

Biologics.

Question 56

An oncolytic virus, such as _____, works by delivering genes that selectively lyse tumour cells.

Answer 56

Talimogene laherparepvec (Imlygic®)

Question 57

A patient with _____ metabolizer status for CYP2D6 would likely experience no benefit from a standard dose of the antidepressant nortriptyline.

Answer 57

ultra-rapid

Question 58

A key limitation of AAV vectors is their small packaging capacity, which is approximately _____ kb.

Answer 58

4.5

Question 59

What is the term for a drug that is inactive until it is metabolised by the body into its active form?

Answer 59

A prodrug.

Question 60

The CRISPR-based therapy Casgevy works by disrupting the enhancer of which gene to reactivate fetal haemoglobin?

Answer 60

BCL11A.

Question 61

What is the primary therapeutic goal of altering susceptibility to a genetic disease?

Answer 61

To reduce the chance of the disease developing or progressing by manipulating environmental or dietary factors.

Question 62

The first in vivo CRISPR editing trial targeted which genetic eye disease?

Answer 62

Leber congenital amaurosis (LCA10).

Question 63

In the UK, Mitochondrial Replacement Therapy has been legally permitted since what year?

Answer 63

2015.