Medical Genetics: Gene Therapy Trials Overview

Questions and Answers

What is the function of nuclease defective Cas9 in genome editing?

To create double-strand breaks in DNA

To facilitate RNA interference

To perform epigenetic modifications (correct)

To enhance gene expression directly

What is a common consequence of unintended mutational effects in genome editing?

Targeted gene amplification

Deletion of functional RNA sequences

Increased fidelity in DNA repair

Alterations to off-target genes (correct)

Which repair mechanism is associated with gene knockouts through CRISPR/Cas?

Transcriptional recombination

Homology-directed repair

Single-strand annealing

Non-homologous end joining (correct)

What is a potential result of HDR when using a template in genome editing?

Creation of a new RNA sequence Signup and view all the answers

Which phenomenon describes chromosome shattering and random rejoining during genome editing?

Chromothripsis Signup and view all the answers

Which application of CRISPR/Cas is involved in creating large DNA deletions?

NHEJ repair Signup and view all the answers

What could be an unintended consequence when using a plasmid repair template in gene editing?

Insertion of foreign DNA Signup and view all the answers

What type of fusion is employed in base editing with gRNA/Cas?

Cytidine deaminase Signup and view all the answers

What are the primary delivery methods for viral vector gene therapy?

Both in vivo and ex vivo methods can be used. Signup and view all the answers

What is a key factor in the effective application of vector selection in gene therapy?

The vector must match the specific disease condition being targeted. Signup and view all the answers

What recent gene editing technique is highlighted for its use in clinical trials?

CRISPR/Cas gene editing. Signup and view all the answers

Which aspect of gene therapy does the module suggest needs critical evaluation?

The outcomes of clinical trials. Signup and view all the answers

What is the most comprehensive description of gene therapy based on the provided content?

It is the use of recombinant genetic material as a therapeutic agent. Signup and view all the answers

How diverse are the conditions currently targeted by gene therapy based on the content?

There is a large breadth of conditions being targeted. Signup and view all the answers

What is the purpose of the FIX Padua (FIX-R338L) transgene in the AAV vector?

To increase blood clotting factor levels Signup and view all the answers

What was the observed range of FIX coagulant activity after vector administration?

14 to 81% Signup and view all the answers

How many participants did not experience any bleeding after vector administration?

9 Signup and view all the answers

What is the cost of Hemgenix (etranacogene dezaparvovec) as reported?

£3,500,000 Signup and view all the answers

What is the date of FDA approval for Hemgenix?

November 22, 2022 Signup and view all the answers

What was the total number of participants in the study mentioned?

10 Signup and view all the answers

Which of the following gene therapies was approved most recently?

Casgevy Signup and view all the answers

What proportion of participants used factor after vector administration?

8 of 10 Signup and view all the answers

What was the primary outcome of the gene therapy for Junctional epidermolysis bullosa (JEB) after one year?

Complete epidermal regeneration and robust skin function Signup and view all the answers

Which component was used in the retroviral vector for the gene therapy process?

LAMB3 cDNA Signup and view all the answers

What does the 'pA' represent in the structure of the retroviral vector diagram?

Polyadenylation signal Signup and view all the answers

In sickle cell disease, which specific mutation occurs in the beta-globin gene?

Glutamic acid to valine Signup and view all the answers

What is a characteristic of beta-thalassemia?

Normal beta-chain production but dysfunctional Signup and view all the answers

What significant approval was noted as a recent breakthrough in gene therapy?

FDA approval of Vyjuvek for dystrophic epidermolysis bullosa Signup and view all the answers

Which of the following therapies is commonly used for managing haemoglobinopathies?

Red blood cell transfusions and iron chelation Signup and view all the answers

What area was biopsied to obtain epidermal stem cells for ex vivo gene therapy?

Palms of the hands Signup and view all the answers

What condition does the retroviral vector encoding adenosine deaminase (ADA) specifically target?

Adenosine deaminase deficiency (ADA-SCID) Signup and view all the answers

What is the primary function of the TREC levels measured in CD3+ cells?

Reflect T cell development Signup and view all the answers

Which gene is implicated in Junctional epidermolysis bullosa (JEB) due to its deficiency?

Laminin 5 Signup and view all the answers

What is a known limitation of the ex vivo bone marrow stem cell correction method for ADA-SCID?

It does not address systemic toxicity from metabolites Signup and view all the answers

What age group is primarily affected in the patient case study of Junctional epidermolysis bullosa (JEB)?

Middle-aged adults Signup and view all the answers

What aspect of the treatment for JEB is highlighted in the research conducted by Maviolio et al.?

Transplantation of genetically modified epidermal stem cells Signup and view all the answers

Which cell type was NOT mentioned in the absolute counts related to PB cells?

CD14+ monocytes Signup and view all the answers

What is the scale for TREC numbers in age-matched controls?

270 ± 130 copies per 100 ng of DNA Signup and view all the answers

Study Notes

Gene Therapy Overview

Gene therapy utilizes recombinant genetic material (DNA, RNA, hybrid molecules) as a therapeutic agent.
Aims to address inherited single gene disorders through various delivery methods, including in vivo and ex vivo.

Aims and Objectives

Understanding the delivery methods of viral vector gene therapy.
Knowing principles behind vector selection and design tailored to specific diseases.
Evaluating outcomes from CRISPR/Cas gene editing applications in clinical trials.
Recognizing a diverse range of conditions targeted by gene therapy in research.

Genome Editing Techniques

CRISPR/Cas Genome Editing: Uses site-directed nucleases (SDNs) for gene knock-out or modification.
Double-strand breaks repaired through non-homologous end joining (NHEJ) or homologous recombination (HDR).
Base Editing: Nuclease-defective Cas9 combined with gRNA to induce specific nucleotide changes.

Off-target Effects of Gene Editing

Off-target mutations involve unintended alterations in genes other than the target.
On-target effects can lead to significant consequences, including large deletions, chromosomal rearrangements, and abnormal mRNA/protein production.

Case Studies in Gene Therapy

Junctional Epidermolysis Bullosa (JEB): Gene therapy using retroviral vectors to correct laminin 5 deficiencies, focusing on epidermal stem cells resulting in successful skin regeneration.
Dystrophic Epidermolysis Bullosa: First topical gene therapy, Vyjuvek, has received FDA approval for treatment.

Hemoglobin Disorders Treatment

Thalassemia: Characterized by globin chain imbalances; treated with transfusions and gene therapy using AAV vectors.
Sickle Cell Disease: Managed via gene therapies that correct the genetic mutation at codon 6.
FDA Approval of Hemgenix: First gene therapy for adults with Hemophilia B, markedly improving factor FIX activity.

Approved Gene Therapies

Multiple gene therapy products have received approval, with significant costs associated.
Notable examples:
- Zynteglo for β-thalassemia.
- Zolgensma for spinal muscular atrophy (SMA).
- Skysona for CALD and Hemgenix for Hemophilia B—the latter reported cost approximately $3.5 million.

Historical Context

The field of gene therapy has evolved significantly, with clinical trials beginning in 1989 and progressing through various phases leading to therapies that are now commercially available.

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Description

This quiz provides an introductory overview of clinical trials involving gene therapy using viral vectors and gene editing techniques for inherited single gene disorders. Designed for students in medical and molecular genetics, it aims to deepen your understanding of the innovative approaches being utilized in this field.