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With this form, you create a step-by-step module on research integrity or ethics. This can be used to provide instruction on a particular topic. You might want to use it for a tutorial, teaching material, case analysis tool, or an educational game.

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Module

Instructions for:ParticipantTrainer

Perspective Participant

What are the steps?

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What is Hunter syndrome?

Hunter syndrome is a rare genetic disorder that primarily affects males. It is part of a group of diseases known as mucopolysaccharidoses or MPS, which are caused by the body's inability to break down certain complex sugars called glycosaminoglycans or GAGs. For people with Hunter syndrome, a lack of the enzyme iduronate-2-sulfatase or IDS, means that GAGs build up inside the body leading to a wide variety of symptoms including developmental issues, physical problems and mental decline. For example:

*Physical development impacts like coarse facial features, thickened skin, enlarged tongue, and joint stiffness.
*Developmental delays in children affecting motor skills, speech, and learning.
*Respiratory problems with frequent respiratory infections, sleep apnoea, and other breathing difficulties.
*Hearing loss.
*Enlarged liver and spleen, leading to abdominal distension.
*Heart problems with heart valve abnormalities and other cardiac issues.
*Skeletal abnormalities like joint stiffness, short stature, and abnormal bone development.

The onset of the disease is usually between the ages of 2 and 4 years and developmental decline is usually evident between the ages of 18 and 36 months.

There is currently no cure for Hunter syndrome, but treatments can help to manage the symptoms and improve quality of life. Options include:

#Enzyme replacement therapy (ERT). Regular, often weekly, infusions of a synthetic version of the missing enzyme can help reduce the buildup of GAGs. However, the enzyme is not able to pass the blood-brain-barrier, so this form of treatment does not help to protect against brain damage.

*Symptomatic treatments for specific issues including physical therapy for joint problems, medications for respiratory and heart problems, and surgical interventions for specific complications.

Despite treatment, those with severe disease usually die in their teens. Those with a milder form of Hunter syndrome might live with more gradual deterioration in health until middle age.

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Justification for this type of research cannot rest purely upon the assessment of harms and benefits for the participants. There are many other factors to take into account when assessing the ethical permissibility of leading-edge gene editing research with humans. Work through the presentation below to reveal some other important factors that might need to be considered.

The assessment of proposals like this is a complex matter and it may demand input from a wide range of perspectives. There are specific technical questions (for instance, regarding what the therapy will involve and the potential for off-target or on-target effects), as well as broader and more general questions, (for instance, ‘does this research need to be done?’ and ‘who stands to benefit from the research?’). The involvement of young children also demands careful consideration, ‘Is children's participation in the research necessary or could the information be obtained in other ways?’;‘What would be the likely consequences of not involving children?’. These considerations require individual, case by case scrutiny, from a committee with wide-ranging expertise.

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The EU’s approach to genome editing is highly precautionary, particularly when it comes to germline editing. Regulations are largely guided by the European Medicines Agency (EMA), which oversees clinical applications of genome editing therapies.
{{{!}} class="wikitable"
{{!}}+
!'''Governance at the international level'''
The governance of gene editing research is not straightforward because it varies across countries, and encompasses legal, ethical, scientific, and societal dimensions. There have been steps towards development of an international regulatory framework. For instance:

The World Health Organization has established advisory committees to provide guidelines on human genome editing. In 2021, the WHO published two reports offering recommendations on the governance and oversight of human genome editing, particularly emphasizing international collaboration and transparency.

!
{{!}}-
!'''Governance at the country level'''

At the country level, there are varying legal frameworks regarding gene editing research, particularly around its use in humans. For instance, some countries in Europe have banned germline editing outright, while others permit research but with stringent oversight. The Genetic Literacy Tracker tracks the development of gene editing regulations around the globe and can be found here: https://crispr-gene-editing-regs-tracker.geneticliteracyproject.org/
![[File:G8.png|thumb|link=Special:FilePath/G8.png]]
{{!}}-
{{!}}'''Self-regulation'''

Some organisations, like the International Society for Stem Cell Research (ISSCR), provide self-regulation guidelines for scientists working with gene editing technologies. These guidelines encourage ethical practices, discourage irresponsible experimentation, and promote high standards of safety.
{{!}}[[File:G9.png|thumb|link=Special:FilePath/G9.png]]
{{!}}-
{{!}}'''Looking to the future'''

As gene editing technologies evolve, governance models are also adapting. Emerging discussions focus on the need for adaptive governance, meaning a flexible framework that can evolve in response to technological advances.
{{!}}[[File:G10.png|thumb]]
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This checklist is intended for use as a supplement to the usual ethics review process regarding matters that are mainly specific to gene editing in humans. All usual aspects of research ethics review will also need to be considered, for instance, the appropriate processing of sensitive data or the involvement of vulnerable persons, like young children. Additionally, the checklist is not exhaustive;there may be other issues pertaining to individual studies that are not included here. Nevertheless, alongside general guidelines and processes, it provides a useful starting point for ethics reviewers.

#Somatic or germline gene editing
##Does the project aim to involve somatic or germline gene editing or both?
##If germline gene editing, does the project comply with national legislation?
##If germline gene editing, what steps have been undertaken to ensure societal acceptability?
##If somatic gene editing, could the intervention affect the germline accidentally?
#Novelty of gene editing in the project
##Does the project use a novel technique, one that has already been tried in humans, or both?
##If this is the first time it has been tested in humans, have comprehensive studies been undertaken in vitro and in animals to demonstrate proof of concept and safety?
##If the technology has already been tested in humans, what do the findings tell us about potential risks and benefits?
#Technological and other risks
##Are risks of on-target effects clearly described and addressed?
##Are risks of off-target effects clearly described and addressed?
##Are risks of genetic mosaicism clearly described and addressed?
##Are risks of immunogenicity clearly described and addressed?
##Are risks associated with the treatment process clearly described and addressed?
##Are risks of incidental findings clearly described and addressed?
#Enhancement and slippery slope
##Is the gene editing to be used purely for therapeutic purposes?
##If for therapeutic purposes, are there risks that the technology could also be applied for enhancement purposes?
##If so, how is this risk addressed?
#Consent
##How is the consent process being managed?
##How is the option to opt out of the procedure being managed?
##Is participant information sufficiently comprehensive and comprehensible so that the potential participants (or their legal representatives) will understand enough about the technology to assess the potential for harms and benefits meaningfully?
##Are the potential participants being offered adequate support and time to reach a decision?
#Data
##What measures and protections are in place to prevent the exploitation of genetic and/or other biological data, for example, for profit?
##What measures and protections are in place to prevent the misuse exploitation of genetic and/or other biological data and leading to, for example, discrimination, harassment, or marginalisation?
#Equity
##Who are the potential beneficiaries of this study?
##Will the resultant therapy or other benefits be broadly accessible?
##How are any matters of potential inequity in access addressed and justified?
#Study justification
##Is there a medical need for this study?
##Might the same objectives be achieved via less risky and/or less costly methods?

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Given what you understand about the associated harms and benefits, do you think this study is ethically justified if the potential for benefits exceeds the potential for harms?

'''Feedback'''

It’s unlikely that the study would be approved or disallowed based on the brief information that was available to you. Proposals that are reviewed by a research ethics committee are normally highly detailed and researchers are expected to address all anticipated ethical issues. If you would ask for changes or for further information, what would that be?

The case study in this module is based upon a real-world study. The case has been adapted here for teaching purposes, but you can read about the real study by following these links:

https://www.genomicseducation.hee.nhs.uk/blog/world-first-gene-therapy-trial-for-hunter-syndrome-opens/

https://themedicinemaker.com/discovery-development/the-worlds-first-gene-therapy-clinical-trial-for-hunter-syndrome

https://b-s-h.org.uk/about-us/news/gene-therapy-trial-for-hunter-s-syndrome-to-begin

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Thank you for taking this irecs module!

Your feedback is very valuable to us and will help us to improve future training materials.

We would like to ask for your opinions:

1. To improve the irecs e-learning modules

2. For research purposes to evaluate the outcomes of the irecs project

To this end we have developed a short questionnaire, which will take from 5 to 10 minutes to answer.

Your anonymity is guaranteed;you won’t be asked to share identifying information or any sensitive information. Data will be handled and stored securely and will only be used for the purposes detailed above. You can find the questionnaire by clicking on the link below.

This link will take you to a new page: [https://eur01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fforms.office.com%2Fe%2FUsKC9j09Tx&data=05%7C02%7CKChatfield%40uclan.ac.uk%7Cbe3ccf952ee04506e25608dd19dcde06%7Cebf69982036b4cc4b2027aeb194c5065%7C0%7C0%7C638695158651948095%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=P5sNoxm3jW6tLABNV7bNiETR3fHQUG2VODMd3wk3r9E%3D&reserved=0 https://forms.office.com/e/UsKC9j09Tx]

Thank you!

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Bostrom, Nick, et Rebecca Roache. « Ethical issues in human enhancement ». In New Waves in Applied Ethics, édité par J. Ryberg, T. Petersen, et C. Wolf, 120--152. Palgrave-Macmillan, 2007. (https://www.darpa.mil/program/insect-allies).

Cohen, Y (2019) Did CRISPR help or harm the first-ever gene-edited babies? Science, 1st August [https://www.science.org/content/article/did-crispr-help-or-harm-first-ever-gene-edited-babies https://www.science.org/content/article/did-crispr-help-or-harm-first-ever-gene-edited-] [https://www.science.org/content/article/did-crispr-help-or-harm-first-ever-gene-edited-babies babies]

Kleiderman, Erika, et Ubaka Ogbogu. « Realigning gene editing with clinical research ethics: What the “CRISPR Twins” debacle means for Chinese and international research ethics governance ». Accountability in Research 26 (9 mai 2019): 257-64. https://doi.org/10.1080/08989621.2019.1617138.

Palazzani, Laura. « Gene-Editing: Ethical and Legal Challenges ». Medicina e Morale 72, no 1 (11 avril 2023): 49-57. https://doi.org/10.4081/mem.2023.1227.

Singh SM. Lulu and Nana open Pandora's box far beyond Louise Brown. CMAJ. 2019 Jun 10;191(23):E642-E643. doi: 10.1503/cmaj.71979. PMID: 31182462;PMCID: PMC6565397.

1 AUG 2019

Smyth, Stuart J., Diego M. Macall, Peter W. B. Phillips, et Jeremy de Beer. « Implications of Biological Information Digitization: Access and Benefit Sharing of Plant Genetic Resources ». The Journal of World Intellectual Property 23, no 3-4 (2020): 267-87. https://doi.org/10.1111/jwip.12151.

The Lancet. « Human Genome Editing: Ensuring Responsible Research ». The Lancet 401, no 10380 (mars 2023): 877. https://doi.org/10.1016/S0140-6736(23)00560-3.

Wei, X., & Nielsen, R. (2019). CCR5-∆ 32 is deleterious in the homozygous state in humans. Nature medicine, 25(6), 909-910.

https://www.nature.com/articles/s41591-019-0459-6

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'''Human enhancement'''

The ability to edit genes raises ethical questions about the potential for "designer babies," where genetic enhancements are made for non-medical reasons. This raises concerns about social inequality, discrimination, and the potential misuse of gene editing technologies.

'''Immunogenicity'''

The use of gene editing tools, especially those involving viral vectors to deliver editing components, may trigger an immune response in the organism. The immune response could limit the effectiveness of the treatment or cause adverse reactions.

'''Off-Target Effects'''

Gene editing tools may unintentionally modify genomic regions other than the target, leading to unintended consequences. Off-target effects could potentially cause new genetic mutations or disrupt the function of other essential genes.

'''On-target effects'''

Gene editing tools may unintentionally modify the target DNA in the wrong way with unwanted deletions or insertions. For instance, the DNA coding for the Cas protein may become built into the DNA target sequence of the cell, which would lead to the gene in question not functioning properly.

'''Mosaicism'''

Genetic mosaicism is the presence of more than one genotype in one individual. Some cells in the target region undergo the desired genetic modification while others still carry the original DNA resulting in a mosaic pattern of edited and unedited cells. This can lead to problems in communication between cells.

'''Slippery slope'''

If genetic enhancement becomes acceptable for certain characteristics, the boundaries of what is considered acceptable will soon be pushed. Additionally, people may begin to feel pressure to enhance to ensure that their children are not disadvantaged in comparison with those who benefit from enhancements.

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