QUESTION 1
PART A
For Part A, read the article by Asher et al. 2020 and the module material, each set of questions is highlighted in red to ensure which sources to use to answer the questions. and answer the questions, the overall word count should not exceed 1500 words. You should include a word count for your answers to Part A.
1. The authors provide some historical context to the gene therapy field in their introduction. According to the authors:
o i.Which scientist is credited as proposing gene therapy as a therapeutic approach?
(1 mark)
o ii.Which journal was the proposal published in?
(1 mark)
o iii.In which year was the proposal published?
(1 mark)
2. What two examples are given of issues that arose with the early viral vectors used for gene therapies? In your answer, state which viral vectors were involved in these issues.
(4 marks)
3. List five different reasons why, according to the authors, adeno-associated viruses (AAVs) are currently the preferred viral vector for gene delivery.
(5 marks)
From your Module Material:
4. Which gene is delivered by Luxturna therapy and what cells does this therapy target?
(2 marks)
5. Rare diseases can arise from premature stop codons in the gene encoding a protein.
o i.Why might a premature stop codon lead to disease?
(2 marks)
o ii.What approach to the treatment of rare diseases that arise from premature stop codons have you encountered in your studies?
(2 marks)
o iii.Explain why the treatment you outlined in part (ii) would be relevant to some people with DMD. Name the treatment that has been developed.
(2 marks)
o iv.Why would such a treatment need to be administered systemically to benefit people with DMD that is caused by premature stop codons?
(2 marks)
6. How do in vivo and ex vivo genetic therapies differ, and what advantages does the manipulation of cells used in ex vivo genetic therapy provide?
(4 marks)
7. Explain how a genetic therapy based on the use of CRISPR-Cas9 could be used to replace a premature stop codon in a gene. In your answer, briefly include the molecular details underlying the CRISPR-Cas9 approach.
(4 marks)
From your reading of section 2 of Asher, et al. (Clinical development for conventional small-molecule drugs vs. gene therapy), according to the authors:
8. In conventional small-molecule trials, how is the correct drug dose established in Phase 1 trials before testing on larger groups of patients with the disease?
(4 marks)
9. Why is it especially important that an optimal dose of the gene therapy virus is already determined in preclinical studies?
(4 marks)
From your study of Module material:
10. Inducible pluripotent stem cells can play an important role in laboratory-based pre-clinical studies to test the cellular uptake and expression of a gene therapy reagent. How could inducible pluripotent stem cells be used to study DMD?
(4 marks)
11. Natural history cohorts can be useful in determining the effectiveness of therapeutics for rare diseases. Why are natural history cohorts used in the context of a trial for a new treatment? In your answer, explain the advantage of having a natural history cohort in the case of a trial for an extremely rare disease.
(4 marks)
From your reading of section 4 of Asher, et al. (Special considerations for DMD gene therapy), according to the authors:
12. Why is DMD a suitable disease for gene therapy?
(4 marks)
13. Why is an AAV-based gene delivery system a good choice for the treatment of muscle in DMD individuals?
(2 marks)
14. What aspects of the AAV and of the dystrophin gene present problems for the development of a gene therapy for DMD?
(3 marks)
15. As part of an evaluation of a viral gene transfer therapy, why is it important to consider data on transduction before deciding on using a higher dose for the treatments? Briefly explain what transduction data would be used, and how the data would influence decisions on doses.
(4 marks)
From your reading of section 5 of Asher, et al. (Case study – clinical development of a novel gene transfer therapy for DMD):
16. Considering their gene therapy agent:
o i.What is the origin of the particular AAV used and why was this selected?
(3 marks)
o ii.What pre-clinical studies are described that suggested that the micro-dystrophin gene constructed by the authors can restore biological function?
(2 marks)
From your study of module material:
17. When developing genetic therapy agents, the potential immunogenicity of the therapeutic protein is an important design consideration.
o i.Which group of cellular proteins would present any micro-dystrophin-derived peptides to the recipient’s immune system?
(1 mark)
o ii.Which type of immune cell is responsible for the monitoring of internal cellular antigens?
(1 mark)
From your reading of section 5 of Asher, et al. (Case study – clinical development of a novel gene transfer therapy for DMD):
18. The authors describe several ongoing and planned clinical trials.
o i.Identify two of the current inclusion criteria discussed by the authors and explain why each was chosen.
(6 marks)
o ii.Which exclusion criterion based upon the presence of antibodies in potential recipients is discussed, and why is this important?
(2 marks)
o iii.From your knowledge of S290, which technique is likely to be used to pre-screen trial participants to ensure that they met the exclusion criterion discussed in your answer to part (ii)? Explain your reasoning.
(2 marks)
19. Three laboratory techniques are being used by the authors to assess transduction, expression, and localisation of the therapeutic micro-dystrophin gene in participants. Identify two of these techniques and specify what is measured with each.
(4 marks)
Part B (20 marks)
Prepare some text for a short section of an information sheet that is to be given to participants in an upcoming trial using the SRP-9001 micro-dystrophin therapy agent. This section of text should provide a summary of the normal cellular function of dystrophin and the design of the micro-dystrophin gene.
You should base your answer on information from the article and your understanding of it. Your section of text should be understandable by a fellow student and it should focus on providing details on:
• the normal cellular function of dystrophin, both within the cell and within the body
• the design of the micro-dystrophin gene, including elements that regulate its expression
• how the micro-dystrophin fulfils the functions of the full-length dystrophin protein.
Note that the total word count for your answer should be no more than 300 words. You should include a word count for your answer.
QUESTION 2
This question will assess your progress towards the following learning outcomes.
• PPS1 design, conduct and report on investigations with human participants and with analytical techniques.
• PPS2 demonstrate an awareness of relevant ethical, privacy, safety and legal aspects related to investigative health sciences.
• PPS3 demonstrate an awareness of the health sciences sector, examples of relevant business and commercial issues, and of the professional skills and behaviours of health scientists.
• a. For learning outcome PPS1, describe in up to 100 words how you have achieved this learning outcome. Your answer should focus on either your ELISA, drug metabolism or clinical microbiology study.
(3 marks)
• b. For learning outcome PPS2, describe in up to 100 words how one aspect of the module materials has raised your awareness of the ethical or safety aspects of investigative health science.
(3 marks)
• c. For learning outcome PPS3, state in up to 150 words how the module materials have raised your awareness of the health sciences sector, for which examples have been presented in the module materials. State whether your reflection is related to changes in your awareness of:
o the health-science sector
o business or commercial issues
o professional skills or behaviours.
Your answers for part (c) should focus on what you have studied and what you have gained from that study.
Your response to this question should be a personal reflection based on your own unique background and experiences.
Rather than just stating that particular things were good or bad, or simply describing what you did, focus on what personal progression you have made in terms of your awareness of the health sciences sector. Give reasons for your views – how your awareness has changed having studied specific module components. Marks will be awarded according to the level of insight, thought and reflection on what you have gained from studying Topics 4–6 of module material.
(4 marks)
