GeneticMedicinesII-Feb5(s) - Copy

Question 1

What is RNA modification therapy?

Answer 1

Targets mRNA to suppress levels or correct/add function.

Question 2

What are antisense oligonucleotides used for?

Answer 2

Treat genetic diseases by decreasing levels of a mutant protein.

Question 3

What are the stability concerns with antisense oligonucleotides?

Answer 3

Originals are not very stable and may have off-target effects.

Question 4

What is the role of DICER in RNAi?

Answer 4

Processes dsRNA to create siRNA.

Question 5

What do siRNA complexes with in the RNA-induced silencing pathway?

Answer 5

Ribonucleases called RNA-induced silencing complexes (RISCs).

Question 6

What is modified by spliceosomes in RNA modification therapy?

Answer 6

Pre-mRNA.

Question 7

How are large genes addressed in RNA modification therapy?

Answer 7

Using two gene transfer vectors encoding independent pre-mRNAs joined by spliceosome-mediated trans-splicing.

Question 8

What are trans-splicing ribozymes?

Answer 8

Catalytic RNA used to trans-splice mRNA.

Question 9

What is the main disorder associated with adenosine deaminase deficiency (ADA-SCID)?

Answer 9

Autosomal recessive metabolic disorder causing immunodeficiency.

Question 10

What is the role of dATP in ADA-SCID?

Answer 10

Inhibits ribonucleotide reductase, preventing DNA synthesis.

Question 11

What are the common treatment options for ADA-SCID?

Answer 11

Bone marrow transplant or enzyme replacement therapy (ERT).

Question 12

What successful gene therapy trials occurred in 2011 for ADA-SCID?

Answer 12

6 patients treated with retrovirus, 3 treatment-free after 10 years.

Question 13

What is Strimvelis® and its approximate cost?

Answer 13

Gene therapy for ADA-SCID costing ~$850k.

Question 14

What is beta-thalassemia?

Answer 14

A common inherited blood disorder caused by mutations in the HBB gene.

Question 15

What type of vector is used for beta-thalassemia gene therapy?

Answer 15

Lentiviral vector, now called zynteglo.

Question 16

What was the outcome of the 2007 beta-thalassemia clinical trial?

Answer 16

One patient failed to engraft, but later updates showed stability.

Question 17

What percentage of Hb contains vector-encoded beta globin in recent trials?

Answer 17

1/3 of Hb.

Question 18

What mutation leads to βE/βO thalassemia?

Answer 18

Point mutation leading to alternative splicing and partial instability.

Question 19

What was a significant risk associated with early gene therapy trials?

Answer 19

Patients developed leukemia in different retroviral trials.

Question 20

True or False: Gene therapy trials for ADA-SCID began in the 1990s.

Answer 20

True.

Question 21

Fill in the blank: RNA modification therapy can utilize _______ to target specific genes.

Answer 21

dsRNA.

Question 22

What is ex vivo gene therapy?

Answer 22

A technique where cells are modified outside of the body and then reintroduced.

Question 23

What is Adenosine deaminase deficiency (ADA-SCID)?

Answer 23

An autosomal recessive metabolic disorder that causes immunodeficiency.

Question 24

What enzyme is needed for the breakdown of adenosine from food?

Answer 24

Adenosine deaminase.

Question 25

What does an increase in dATP inhibit?

Answer 25

Ribonucleotide reductase.

Question 26

What is the consequence of inhibiting ribonucleotide reductase?

Answer 26

Prevents DNA synthesis, so cells are unable to divide.

Question 27

Which cells are highly susceptible to ADA-SCID?

Answer 27

Developing T cells and B cells.

Question 28

What treatments do patients with ADA-SCID receive?

Answer 28

Bone marrow transplant or enzyme replacement therapy (ERT).

Question 29

What was the outcome of the 2011 retrovirus trial for ADA-SCID?

Answer 29

6 patients, 3 still ERT treatment free after 10 years.

Question 30

What was the outcome of the 2009 retrovirus trial for ADA-SCID?

Answer 30

10 patients, 8 still ERT treatment free after 4 years.

Question 31

What was used to condition patients prior to cell reintroduction in successful therapies?

Answer 31

Busulfan.

Question 32

What was ineffective in conditioning patients prior to cell reintroduction?

Answer 32

Melphalan.

Question 33

What did the successful therapies result in for ADA-SCID patients?

Answer 33

Increased T-cell counts and normalized immune function.

Question 34

When did trial attempts for ADA-SCID begin?

Answer 34

In the 1990s.

Question 35

What was the result of early successes in 2000 for ADA-SCID?

Answer 35

10 patients with functioning immune systems.

Question 36

What happened to patients in different retroviral trials for ADA-SCID?

Answer 36

Developed leukemia.

Question 37

What type of cells are targeted in ex vivo gene therapies?

Answer 37

CD34+ cells.

Question 38

What is the commercial name of the gene therapy for ADA-SCID?

Answer 38

Strimvelis®.

Question 39

What is beta-thalassemia?

Answer 39

A relatively common blood disorder caused by a mutation in the HBB gene.

Question 40

What can occur in individuals with a single mutation of the HBB gene?

Answer 40

They may develop anemia.

Question 41

What does the vector in beta-thalassemia gene therapy contain?

Answer 41

A mutated beta-globin gene with anti-sickling properties.

Question 42

What is βE/βO thalassemia?

Answer 42

The most common intermediate form of beta-thalassemia.

Question 43

What causes the βE allele in βE/βO thalassemia?

Answer 43

A point mutation leading to alternative splicing.

Question 44

What type of vector is now called zynteglo?

Answer 44

Lentiviral vector.

Question 45

What was the outcome of the 2007 clinical trial for beta-thalassemia?

Answer 45

2 patients, one failed to engraft.

Question 46

What was the update in 2015 regarding beta-thalassemia patients?

Answer 46

Seven years later, still transfusion independent with stable hemoglobin levels ~10 g/dl.

Question 47

When was zynteglo approved in Europe and the US?

Answer 47

Approved in Europe Dec 2019, US Aug 2022.

Question 48

What percentage of Hb contains vector encoded beta globin in successful cases?

Answer 48

1/3.

Question 49

What may have contributed to the success of beta-thalassemia gene therapy?

Answer 49

Dominance of a large clone having retroviral integration into the HMG2A gene.

Question 50

What is the role of the truncated protein overexpressed due to retroviral integration?

Answer 50

Involved in base repair and acts as a transcriptional regulating factor.

Question 51

What is the purpose of the LentiGlobin BB305 vector?

Answer 51

Prevents polymerization of the βAT87Q-globin variant ## Footnote This vector includes cis-regulatory elements that confer high, erythroid-specific expression.

Question 52

What type of mutation is associated with sickle cell disease?

Answer 52

Autosomal recessive mutation in HBB ## Footnote Hemoglobin S will polymerize upon deoxygenation, leading to the disease.

Question 53

What happens to red blood cells (RBCs) in sickle cell disease?

Answer 53

Stiffening and sickling of RBCs ## Footnote This occurs due to polymerization of hemoglobin S.

Question 54

What were the results noted 15 months post-autologous hematopoietic stem cell transplant for sickle cell disease?

Answer 54

No recurrence of sickle crises and correction of the biologic hallmarks of the disease ## Footnote Subsequent trials were initiated following this observation.

Question 55

Why was the trial temporarily suspended in February 2021?

Answer 55

Patient developed leukemia ## Footnote The trial resumed in July 2021.

Question 56

What is Lyfgenia approved for, and when was it approved?

Answer 56

Approved for junctional epidermolysis bullosa in December 2023 ## Footnote The treatment costs $3.1 million.

Question 57

What are the consequences of junctional epidermolysis bullosa?

Answer 57

Chronic, painful and untreatable wounds leading to skin cancers, infection, and sometimes death ## Footnote This condition is linked to LAMB3 mutation-laminin subunit.

Question 58

What percentage of the body experienced complete epidermal loss in the 7-year-old patient?

Answer 58

80% ## Footnote This highlights the severity of the condition.

Question 59

What was sequenced in the treated skin of the patient with junctional epidermolysis bullosa?

Answer 59

Mutagenesis ## Footnote Researchers searched for clonal selection and antibodies.

Question 60

What is the name of the clinical trial mentioned in January 2017?

Answer 60

Hologene 5 Clinical Trial ## Footnote Specific details about the trial's focus are not provided.