Gene Editing Case Study with Human Application
InstructionsGene Editing Case Study with Human Application
The aim of this module is to facilitate reflection upon the ethics issues associated with the development and use of gene editing in humans.
Learning outcomes
At the end of this module, learners will be able to:
- Identify and analyse the ethics issues and dilemmas associated with an example research proposal.
- Make suggestions for how the ethics issues might be addressed.
- Identify ethics guidelines and policies that are relevant to the proposed research.
Video Transcript
In humans, gene therapy via gene editing is a rapidly growing field of research with many potential benefits for health and wellbeing. It involves the editing of genes to modify or knock out specific genes to achieve desired traits, to correct genetic defects, to treat or prevent disease, or to enhance cellular functions.
In this module we consider an example proposal for a research project that is based upon a real-world study. The study aims to trial gene therapy for Hunter syndrome in a small group of young children. As you work through the module, we invite you to consider the ethics issues that are associated with this type of study from a variety of perspectives as well as how they might be addressed. We begin with some information about the disease.
What is Hunter Syndrome?
Watch the video below to learn about Hunter syndrome, its treatments and effects.
Video Transcript
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.
Hunter Syndrome Poll
Now that you know a little about the syndrome, imagine that you are the parent of a 12-month-old child who has been diagnosed with severe Hunter syndrome. Your child is being offered the chance to try a new experimental therapy for the disease, but the treatment is untested in humans.
Are you likely to agree to their participation? Please select a response and then check to see how others have responded.
Feedback
Decisions about whether or not to participate in studies that are testing novel interventions can be challenging for anyone. Why not just let others take the risk in an experimental trial and wait to see what the outcomes are? For the parents or guardians of young children who are unable to consent for themselves, the decision-making is much more complex. As you work through the rest of the module, see whether you change your mind about your response.The Research Proposal and Ethics Approval
Let’s find out more about the proposed study. While watching the next video, imagine that you are a member of an ethics review committee and your role is to make an assessment about whether or not to approve the study, to ask for changes to be made / further information, or to disallow the study. Make a note of any points or questions that arise for you.
Video Transcript
The research proposal
Over the past 7 years, a multinational group of scientists have been investigating the potential use of hematopoietic stem cell gene therapy as a treatment for Hunter syndrome. Hematopoietic stem cells (HSCs), also known as blood stem cells, are immature cells in the bone marrow that can develop into all types of blood cells. They have two key characteristics:
- Self-renewal. HSCs can divide and maintain themselves over long periods of time.
- Multipotency. HSCs can generate daughter cells that can differentiate into all blood cell types.
Pre-clinical studies undertaken in rodents have successfully demonstrated the potential of the HSC gene therapy to correct Hunter syndrome in the body and normalise brain pathology. Rodents with the syndrome, treated with the HSC gene therapy, showed dramatic improvements in their condition.
Now the same research group aims to test the approach in humans. This will be the first time it has been tested in humans. It is anticipated that the treatment via genetic manipulation of the patients’ own cells will result in the delivery of increased amounts of the IDS enzyme. As well as clinical efficacy, the study aims to evaluate the HSC gene therapy’s safety and tolerability, and pharmacodynamic effects.
The gene therapy involves collection of HSCs from the patients and inserting a working copy of the defective gene into their HSCs using a lentiviral gene therapy vector. The modified HSCs will then be infused back into the patient to engraft in the bone marrow. If engraftment of modified HSCs in the bone marrow is successful, these cells start to produce daughter blood cells. The daughter blood cells will contain a working copy of the IDS gene and the IDS enzyme will be distributed throughout the body, including the brain.
The study aims to recruit up to ten patients diagnosed with severe Hunter syndrome, aged between 3 months and 24 months at time of enrolment, and who have not yet shown developmental decline.
The treatment process will occur in 3 stages:
- Stem cell collection.
- Conditioning to prepare the bone marrow using chemotherapy.
- Infusion of gene-modified cells.
The study duration will be 24 months and the young patients will be checked at regular intervals during this period.
The Discussion
There may be opposing views on the research ethics committee about whether this study can be approved. It is certainly a proposal that demands careful ethical scrutiny. In the audio below you will hear from some REC members who discuss some of the issues that need to be considered. Check to see whether they address all of the points or queries that you noted.
Discussion Transcript
Research ethics committee discuss the proposal
REC member 1
The thing the concerns me most about this proposal is that it will involve very young and incredibly vulnerable children. They can’t consent to their participation, so that responsibility lies with their parents / legal guardians.
REC member 2
Don’t you think the parents or guardians are in the best position to decide what is in the best interests of their children?
REC member 1
I think the parents might feel pressure to consent to participation because they believe the study offers their child the best chance of recovery and that, by participating in this sort of study, their child will get better medical care and attention.
REC member 3
And the parents are liable to feelings of guilt either way, whether they consent or not. If they don’t consent, then their child will likely die during their teens. If they do consent, and things go wrong, they might feel responsible for making things worse.
REC member 4
I believe we have a moral duty to pursue research like this. There are more than 7,000 rare genetic diseases that we know of and about three-quarters of these affect children. If improvements are to be made in the care and treatment of these children, research is essential.
REC member 2
I can see the need for the research, but I wonder why the children have to be so young. Can’t the therapy be tried in adults or older children first?
REC member 1
I guess that’s because the study must be undertaken before any serious decline occurs, and with severe Hunter syndrome, that is only the case for the very young. Plus, the earlier the treatment occurs, the less damage that can be done. The ideal would be to stop the disease before any damage.
REC member 3
We must remember that gene editing is still highly experimental, so there might be a number of technical risks, and some of these risks might not even be known. This means that the children could suffer from serious consequences if the procedure fails or even if the procedure is successful. The parents will need to be fully informed about both the technology and the risks. There’s a chance that the treatment might make their child suffer even more than they would have done.
REC member 2
Yes, that’s true. What about the risks of off-target effects, or on-target effects, immunogenicity or genetic mosaicism? If we don’t know the precise risks, how can we decide whether the potential benefits outweigh the risk of harms to the children?
REC member 4
I think we can feel somewhat reassured by the fact that this is the same group that has undertaken the earlier testing in animals. They have developed and perfected the technique for this gene therapy, and they are confident that they are now in the position to move to testing in humans.
REC member 1
I agree. That does help to provide some reassurance, but there’s no way that all risks can be avoided. I would like to know what steps are being taken to minimise those risks.
REC member 4
We also need to consider the harm the potential for harm associated with the treatment process itself. Both stem cell collection and chemotherapy involve risks. Chemotherapy for bone marrow conditioning can lead to all of the well-known side effects like hair loss, nausea and vomiting, fatigue, and a compromised immune system. Participating in the trial will inevitably increase suffering in the short term.
Did the committee raise all of your concerns? In the next step we touch on some other points, but first, we ask you to think about balancing potential harms and benefitsIs the Research Justified?
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.
A Checklist for Research Ethics Committees
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.
1. Somatic or germline gene editing
a. Does the project aim to involve somatic or germline gene editing or both?
b. If germline gene editing, does the project comply with national legislation?
c. If germline gene editing, what steps have been undertaken to ensure societal acceptability?
d. If somatic gene editing, could the intervention affect the germline accidentally?
2. Novelty of gene editing in the project
a. Does the project use a novel technique, one that has already been tried in humans, or both?
b. 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?
c. If the technology has already been tested in humans, what do the findings tell us about potential risks and benefits?
3. Technological and other risks
a. Are risks of on-target effects clearly described and addressed?
b. Are risks of off-target effects clearly described and addressed?
c. Are risks of genetic mosaicism clearly described and addressed?
d. Are risks of immunogenicity clearly described and addressed?
e. Are risks associated with the treatment process clearly described and addressed?
f. Are risks of incidental findings clearly described and addressed?
4. Enhancement and slippery slope
a. Is the gene editing to be used purely for therapeutic purposes?
b. If for therapeutic purposes, are there risks that the technology could also be applied for enhancement purposes?
c. If so, how is this risk addressed?
5. Consent
a. How is the consent process being managed?
b. How is the option to opt out of the procedure being managed?
c. 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?
d. Are the potential participants being offered adequate support and time to reach a decision?
6. Data
a. What measures and protections are in place to prevent the exploitation of genetic and/or other biological data, for example, for profit?
b. 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?
7. Equity
a. Who are the potential beneficiaries of this study?
b. Will the resultant therapy or other benefits be broadly accessible?
c. How are any matters of potential inequity in access addressed and justified?
8. Study justification
a. Is there a medical need for this study?
b. Might the same objectives be achieved via less risky and/or less costly methods?
