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Public acceptability of gene therapy and gene editing for
human use: A systematic review
Juliette Delhove1-3, Ivana Osenk4, Ivanka Prichard4, and Martin Donnelley1-3
1Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide,
Adelaide, SA, 5005, Australia;
2Robinson Research Institute, University of Adelaide, Adelaide, SA, 5005, Australia;
3Respiratory and Sleep Medicine, Women’s and Children’s Hospital, 72 King William Rd,
North Adelaide, SA, 5006, Australia;
4College of Nursing and Health Sciences, Flinders University, Bedford Park, SA, 5042,
Australia
Correspondence to juliette.delhove@adelaide.edu.au
Work performed in Adelaide, South Australia
Short Title: Acceptability of gene therapy/editing
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Abstract
Gene therapy and gene editing technologies are complex and it can be difficult for the public
to understand their possible benefits or side-effects. However, patient and public support are
critical for the successful adoption of any new technology. Given the recent advances in gene
therapy and gene editing, their potential clinical benefits, and the significant attention that has
been given to the first-known successful attempt at permanent and heritable changes to the
human genome, a systematic review was performed to assess beliefs and attitudes towards gene
therapy and gene editing for human use, and to highlight the factors that influence acceptability.
A systematic search following PRISMA guidelines was undertaken in April 2018 to identify
papers examining opinions and attitudes regarding the acceptability of gene therapy and gene
editing. Overall, 1561 records were retrieved from four databases (Ovid Medline, PsycINFO,
Scopus, and Web of Science). Duplicates were removed, and titles and abstracts independently
screened, leaving 86 full-text articles assessed for eligibility. Following full-text review, 33
were included, with 5 articles added after forwards/backwards searching. An additional 3
articles were added following an updated search in March 2019 (total n = 41).
Findings from the studies were integrated according to common themes: the impact of
demographics; risks versus benefits of success; treatment specifics (e.g., medical versus other
reasons; disease severity and status; somatic versus germline; mode of delivery); moral or
ethical issues; and changes with time. In general, perceptions were positive, particularly for
medical reasons and fatal diseases, but were also influenced by perceived risk. Somatic
therapies had higher levels of acceptability than germline therapies. While available in various
forms, limitations exist in the measurement of perceptions of gene therapy and gene editing.
Treatment acceptability is essential for future clinical trials, so it is important for scientists and
clinicians to be clear about the risks and benefits of these technologies, and how these are
communicated to the public, while encouraging education about genetic therapies to a broad
range of individuals.
Keywords: Gene therapy, gene editing, acceptability, perceptions, communication, education
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Introduction
Genetic diseases are conditions caused by one or more mutations in the genome, and are ideal
targets for gene therapy or gene editing; treatments designed to correct the function of the
abnormal gene1. Gene therapy achieves this by adding a correct copy of the gene into the
genome of the cells in the target organ or tissue, while gene editing alters the genome at a
specific location to correct or alter the genetic sequence2. The premise of both of these
therapeutic approaches is that the presence of the modified gene enables the expression of a
correctly functioning protein, eliminating the cause of the disease and improving whole organ
function.
Gene therapy and gene editing are ideally suited to monogenic inherited disorders in which
mutations in a single gene are responsible for causing disease. They are also typically targeted
at rare diseases for which effective treatment options are not available, and for which premature
death occurs (e.g., haemophilia, cystic fibrosis). Gene therapy typically uses a vehicle—termed
a gene vector—to transfer a correct copy of the gene of interest into target cells. Viral and non-
viral gene vectors have been developed over the last 30 years to treat a range of intractable
diseases including severe combined immunodeficiency (SCID)3, haemophilia4, Wiscott-
Aldrich syndrome5, metachromatic leukodystrophy (MLD)6, spinal muscular atrophy7, and
cystic fibrosis (CF)8,9. Recently, Luxturna (Spark Therapeutics) became the first FDA approved
prescription gene therapy, treating Leber’s congenital amaurosis, an inherited retinal disease
caused by mutations in the RPE65 gene. Others such as Strimvelis (GlaxoSmithKline) for
SCID, and Glybera (uniQure) for hereditary lipoprotein lipase deficiency, have been marketed,
but have faced challenges due to cost10,11. While ex vivo gene editing approaches have been
developed for diseases such as haemophilia12,13 and immunodeficiencies14, few successful in
vivo techniques have been reported, primarily due to challenges associated with the delivery of
the gene-editing reagents to the target cells15.
While gene therapy and gene editing offer real hope for lasting benefit or a cure for these
diseases, the delivery process and the potential for permanent changes to the host cell genome,
do have potential or actual risks. A 1996 gene therapy clinical trial for X-linked SCID—a
disease characterized by a lack of the IL-2 receptor that results in an impaired adaptive immune
system—used a γ-retroviral vector to deliver the IL-2 receptor gene, and resulted in improved
long-term immune reconstitution and correction of the primary immunodeficiency. However,
25% of patients developed T cell acute lymphoblastic leukaemia16,17, an unexpected
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consequence of the vector inserting itself upstream of the proto-oncogene LMO2, resulting in
its expression 17. Gene vector designs have improved in the last 15 to 20 years, and these
adverse events are now better understood and deemed extremely unlikely. However, risks
remain and there are still some uncertainties about the actual risk involved. For example,
Hampel and colleagues noted that “both the chances and the risks of this technology are still
relatively hypothetical”18. In contrast, risk in other areas of medicine such as organ
transplantation and stem cell therapies has become more acceptable19, likely because the risks
involved in those procedures are better understood. This suggests that the overall risk is a
combination of actual and perceived risks.
There are also several ethical and philosophical issues related to gene therapy and gene editing.
Both can be targeted to the somatic cells, any cell other than the reproductive cells, or to the
germline cells, the reproductive cells that pass their genetic material onto their progeny. Any
risks and consequences arising from somatic cell gene transfer is restricted to that particular
individual. Germline gene transfer differs in that it permanently alters the sex cells of the
organism. Germline alterations would be passed onto future generations, and these therapies
might therefore have a much wider impact than just the treated individual20. Many researchers
consider germline alterations to be an ethical line that should not be crossed21. While rare and
intractable diseases are the main target of gene therapies, a future use might be functional
enhancement. For example, in the future it may be possible to add or alter genes responsible
for strength, endurance, speed, longevity, intelligence, hair or eye colour, or other physical
traits, for non-therapeutic benefit. However, the ethics of these modifications remains
questionable. As such, the ethical and moral implications of genetic therapies are likely to
influence people’s perceptions towards gene therapy and gene editing.
Overall, gene therapy and gene editing technologies are complex processes and it can be
difficult for the public to understand their mechanisms and possible benefits and side-effects
without education and clear communication22. However, both patient and public support is
critical for the successful adoption of a new technology. Since gene therapy can produce
permanent genetic changes, carries some inherent risks, and would ultimately be delivered to
children and young patients, it is important to comprehensively assess the acceptability of gene
therapy and gene editing for human use. Understanding the perceptions that people broadly
hold regarding the potential risks of gene therapy and gene editing for human use is critical to
consider the future viability of these treatments. In addition, patients themselves are integral
stakeholders to the uptake of emerging genetic medicines. Thus, an understanding of specific
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factors that might influence perceptions of these technologies (e.g., mode of delivery, how
therapeutic efficacy is assessed) is also essential.
Researchers have previously reviewed attitudes to biotechnology23, gene therapy24, and gene
editing25, however, given the recent and rapid advances in these fields, and their increasing
potential to provide substantial clinical benefit, a comprehensive systematic review was
deemed essential to assess the beliefs and attitudes towards gene therapy and gene editing for
human use. The aim of this systematic review was to provide a broad understanding of the
perceived acceptability of gene therapy and gene editing for human use and to highlight factors
that influence acceptability.
Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement was followed26. The research question, search strategy, and selection criteria were
all predefined. Critical appraisal of the articles and methods for data analysis and synthesis are
outlined below.
Search strategy
A systematic search was undertaken on 17 April 2018 and updated 6 March 2019 to identify
papers that examined opinions and attitudes regarding the acceptability of gene therapy and
gene editing. The focus was on examining perceptions of gene therapy within a broad
population, with a specific focus on the ‘public’, and exploring views on gene therapy and gene
editing including perceptions, attitudes, and acceptability. A search strategy was developed in
consultation with a Health Sciences Librarian to increase search sensitivity. The following
search string was adapted across four core databases: ((public OR lay OR popular* OR countr*
OR communit* OR patient* OR carer* OR caregiver* OR "care giver"* OR personal OR
parent*) NEAR/10 (attitude* OR accept* OR opinion* OR perception* OR view* OR belief*))
AND ((gene OR genes OR genetic* OR gene-based) NEAR/1 (addition OR edit* OR therap*
OR treat* OR transfer* OR repair* OR replace* OR medicine*)). Databases used were Ovid
Medline, PsycINFO, Scopus, and Web of Science.
Selection criteria
Studies were included if they were full-text, peer-reviewed articles that presented data on
people’s perceptions, attitudes, opinions or views on the acceptability of gene therapy or gene
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editing for human use. Qualitative, quantitative, and mixed-methods studies that presented
primary data were included to gain a greater understanding of the research in this area. Papers
from broad samples (e.g., the general population, parents, students, or those in STEM-related
jobs) as well as ones that examined gene therapy in health, medical, and cosmetic settings were
included. Studies were excluded if they were not peer-reviewed or available in English; if they
did not measure perceptions, views, opinions or attitudes regarding gene therapy for humans;
or if they focused solely on stem cell therapy, genetic testing, sex selection, or genetic
enhancement without gene therapy. Studies that examined perceptions or attitudes towards
gene therapy solely for agricultural purposes or animals were excluded. No date restrictions
were applied.
Study selection
Overall, 1561 records were retrieved from searches on MEDLINE (n = 376), PsycINFO (n =
33), Scopus (n = 745), and Web of Science (n = 407); see Figure 1 for PRISMA diagram.
Duplicates (n = 678) were removed and two authors (IP, MD) independently screened the titles
and abstracts of the remaining 883 records according to the stated inclusion and exclusion
criteria. A further 797 articles were removed and 86 full-text articles were assessed for potential
eligibility. Based on the full-text review, 50 were excluded with reasons recorded (see Figure
1), and 33 from the initial search and a further 3 from the updated search were included (see
Tables 1-3 for a summary of all included articles). Forwards and backwards reference searches
were carried out on all included studies, and an additional 5 articles were identified, resulting
in a final total of 41 studies.
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Figure 1: PRISMA flow diagram of study selection.
Critical appraisal and data synthesis
All included studies were critically appraised by two independent researchers for
methodological quality using the Standard Quality Assessment Criteria for Evaluating Primary
Research Papers from a Variety of Fields27. Where applicable this was supplemented with
items from the Evaluation Tool for Qualitative Studies28. Average quality rating scores were
calculated for each study (score range 0–1). Articles with scores ≤ 0.5 were considered low
quality, with a substantial number of unfulfilled checklist criteria. Articles with scores between
0.51 and 0.8 were considered medium quality, and those with a score > 0.8 were considered
high quality. Studies were not excluded or weighted in the results based on the allocated quality
scores.
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Results
Study characteristics
Forty one studies were included in the review (25 quantitative, 2 qualitative, and 14 mixed-
method). Studies were not excluded based on the weight of evidence provided, as it was
deemed essential to provide a current and complete picture of all of the evidence to date.
Methodological heterogeneity was high across all of the included studies. Studies were
conducted in a range of locations, with the UK (11), USA (10), Australia (6) and Japan (6)
featuring most commonly. Articles were published from 199229 to 201930: five studies29,31-34
were published before 2000, 1418,19,35-46 between 2000 and 2010, and a further 2330,47-67 from
2011 onwards, demonstrating the increasing level of awareness, scientific interest and financial
support for these recent advancements in gene therapy. The number of participants in each
study varied from 2238 to a large public opinion poll of 13,201 people in China62.
Participants in the studies were from a range of sources, including; participants involved in
gene therapy trials32, international samples30,47,55,57, national samples18,39,40,42,43,60,62-65,67, people
recruited from the general public34,35,38,51,52,59,63, students33,38,45,49,52,53,56, conference or public
scientific engagement event attendees35,58,59,66, teachers54, patients36-38,41,44,46,61, parents of
children with a disease19,38, and health practitioners36,46,48,52. Five of the studies utilised online
data collection methods50,51,55,63,65. Ten studies (all from 2016 onwards) specifically examined
gene editing30,55,57-60,63,64,66,67.
The majority of articles were rated as being of medium quality (n = 24), with eleven studies
rated as high quality, and the remaining six rated as low quality. Insufficient information
regarding study design and data analysis procedures were the main reasons for low-quality
study ratings.
Findings from all the studies were integrated such that perceptions towards gene
therapy/editing were synthesised and discussed according to common themes (see Table 1).
These were: the impact of demographics; treatment specifics; risks versus benefits of success;
ethical or moral issues; trust, fears or concerns; and changes over time.
Impact of demographics
Demographics impacted the overall acceptability of gene therapy, with studies investigating
the impact of knowledge/education, gender, religion, and age.
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Knowledge/education
Twenty-four studies examined the impact of knowledge of gene therapy on levels of
acceptance. Ten studies compared clinician/scientist/biology or medical student perceptions
with those of the general public29,31,33,35,43,48,52,53,62,66, eight measured differences in self-
reported or tested genetic knowledge18,39,49,54,60,64,65,67), and a further ten examined differences
in self-reported education levels39,40,42,47,51,53-55,62,63.
The impact of career was mixed, with four studies finding that science-oriented careers were a
significant predictor of greater levels of acceptance of gene therapy29,31,35,62, whilst six studies
found little to no relationship33,43,48,52,53,66. In a recent study, Ganne et al. (2015) also reported
no difference in the acceptance of genetic research between eye care professionals, optometry
students and the general public, reporting an average 70% approval rate across all three
samples52.
Self-reported and tested knowledge of genetics was found to positively impact the acceptance
of gene therapy. For example, Cebesoy et al. (2016) reported that pre-service teachers with a
high self-reported level of knowledge had greater levels of acceptance towards gene therapy54.
Similarly, Crne-Hladnik et al. (2012) demonstrated that female students with higher scores on
a genetics knowledge test were more likely to perceive both somatic and germline gene therapy
as useful49. However, in contrast, Evans and colleagues (2005) found that self-reported
knowledge of genetics did not predict acceptance of gene therapy for a variety of applications39.
Chen et al. (1999) noted that positive attitudes do not necessarily indicate that students have
better knowledge of biotechnology, but rather that they are not aware of the risks33. In relation
to gene editing, Uchiyama et al. (2018) found that despite self-reported low public awareness
and inadequate understanding about gene editing, respondents thought that targeting disease-
related genes was acceptable67.
In relation to education levels, increased education levels were found to be a significant
predictor of greater levels of gene therapy support in seven studies40,47,51,54,55,62,63, whilst two
studies found no relationship39,53, and one reported a negative relationship42. For example,
Weisberg and colleagues (2017) reported that individuals with high school as their highest
education level were less accepting of gene therapy than those with a college degree or higher63.
In contrast, Barnett et al. (2007) found that both education level and attentiveness to issues
around genetics were significant negative predictors of perceptions towards gene therapy42.
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Gender
Eighteen studies examined the impact of gender. Of those a total of 14 articles determined that
women were less approving of gene therapy18,34,39,42,45,47,49,53-55,57,63-65. For example, Napolitano
et al. found that 58% of men and 40% of women supported somatic therapy, while 23% of men
and only 16% of women expressed support for germline therapy34. Although Napolitano et al.
(1999) did note gender-based differences for somatic and germline therapies, they did not
detect an association of gender with acceptability towards specific applications34. One study,
Liu et al. (2011), determined that gender did not impact acceptability within their cohort of
oncology physicians and nurses48, and a further two publications mirrored the sentiment that
gender had no significant impact upon gene editing30,66. Only a single study found women to
be significantly more accepting of gene therapy compared to men62. However, this was context
dependent, with the applications being 1) therapy in children with an inherited disease and, 2)
germline modification.
Religion
Religious affiliations of respondents were considered in ten studies18,39,46-48,51,53,55,60,64.
Religiosity was found to be a negative predictor of acceptability of gene therapy in eight of
these studies18,39,46,47,51,55,60,64. For example, Scheufele and colleagues (2017) determined that
respondents with no religious affiliation reported greater support for gene therapy treatment
applications compared to those with religious beliefs60. Similarly, both Hudson and Orviska
(2011), and McCaughey et al. (2016) found religious status to be a negative predictor of the
acceptance of gene therapy for a variety of applications47,55. In contrast, both Xiang et al. (2015)
and Liu et al. (2011) reported that religion was not related to attitudes toward genetic
applications48,53.
Age
Overall, 26 of the 41 studies contained data on age18,31,34-38,40,43,45,47,49,51-55,57,59,61-67, but only
nine specifically reported on its relationship to perceptions of gene therapy. An inverse
relationship between age and acceptability of gene therapy was noted in four of the
studies47,55,63,64, with younger participants being more accepting of gene therapy than older age
groups. In contrast, one study found that older participants (31 years and older vs 18-30 years)
had a more positive attitude toward gene transfer than younger participants, describing it as
“amazing”61. The remaining four articles that examined age indicated that it had no effect on
attitudes towards either gene therapy42,48 or gene editing57,66.
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Disease status
Weisberg and colleagues (2017) found no differences in levels of gene therapy acceptance in
those affected with a genetic disease or with a family history of genetic disease63. Similarly,
Iredale and colleagues (2013) found no difference in the levels of support for gene therapy for
medical applications between the public and those with cystic fibrosis (CF), but noted that
families of those with CF were qualitatively more enthusiastic in their support of germline gene
therapy (i.e., “Once it is gone you would be glad to see the back of it. I would be in favour of
that”)38.
Treatment specifics
This theme examined a range of factors related to treatment, and how they affect people’s
perceptions. These included: medical versus non-medical applications of the technology,
disease severity and status, acceptability of somatic and germline gene therapy, and mode of
delivery.
Medical versus non-medical reasons for gene therapy or gene editing
A total of 21 studies specifically examined people’s perceptions of gene therapy for medical
(i.e, treatment or risk reduction) reasons in direct comparison to non-medical (i.e., appearance-
related or enhancement) applications30,31,34,35,38-40,43,50,51,53-58,60,62,64-66. Overall, 15 studies asked
respondents their opinion on whether generalised medical vs. minor physical vs.
appearance/enhancement applications should be accepted30,31,35,38,39,43,50,55-58,60,62,64,66. Six
studies compared the perceptions of gene therapy for specific applications: debilitating medical
conditions (e.g., cystic fibrosis, cancer, HIV, neuromuscular disease, LCA, Parkinson’s
disease, sickle cell disease), mental illness (e.g., depression, schizophrenia, attention deficit
disorder), minor physical conditions (i.e., cleft palate, diabetes, obesity), and non-medical
reasons (intelligence enhancement, physical attributes, individual characteristics)34,40,51,53,54,65.
Across almost all 21 studies, in general there was substantially less support for the use of gene
therapy for non-medical purposes compared to medical applications. For example, Napolitano
and Ogunseitan (1999) investigated 13 different applications for gene therapy, finding greater
support for treating a variety of medical and mental health issues (heritable diseases: 70%;
mental retardation: 78%; delayed physical deformity: 77%), compared to both personality and
appearance-related applications (baldness: 11%; hyperactivity: 29%; obesity: 32%)34.
Robillard and colleagues (2014) found 93% of respondents believed it was acceptable to use
gene therapy for Leber Congenital Amaurosis (LCA)(severe blindness at birth), compared to
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only 35% who believed it should be used to enhance memory51. Wang et al. (2017) reported
greater acceptance of gene therapy for the treatment of fatal diseases from both clinicians and
the public (83% and 88%, respectively) compared to gene therapy for enhancement purposes
(32% and 39%, respectively)62.
One qualitative study was conducted using semi-structured interviews to examine the
differences between medical and enhancement purposes for gene therapy. Iredale et al. (2003)
found that people were more strongly opposed to the use of gene therapy for enhancement
purposes, stating comments like “scientists have better things to do than to waste time on
that”38. These opinions were echoed in more recent studies on the perceptions of gene editing,
for example Scheufele et al. (2017) found 59% of respondents expressed support for human
gene editing to treat human medical conditions, compared to 33% who expressed support for
using these techniques to enhance or improve human abilities60. Furthermore, Gaskell et al.
(2017) reported that 75% of respondents’ reported positive evaluations of gene editing
technology for adult therapy (e.g., it would lead to “improvements to quality of life”), and only
26% of respondents’ comments were positive for the use of gene editing for adult
enhancement57.
Only three of the 21 studies found little indication of public discomfort with using gene therapy
for what is deemed to be genetic enhancement/improvement of humans. An early study by
Macer and colleagues (1995) reported that more than 50% of participants from both India and
Thailand supported enhancement of physical characteristics in humans31. More recently, Van
Lieshout and Dawson (2016) asked two small samples of Australian high school students
(sample 1, n = 22; sample 2, n = 19) their position on somatic gene therapy to fight serious
diseases (both samples), minor diseases (sample 1), or to enhance humans (sample 1). For
sample 1, 36%, 50% and 59% were in favour of somatic gene therapy to fight serious diseases,
minor diseases, and human enhancement respectively. In sample 2, 73% were in favour of
somatic gene therapy to fight serious diseases56. Only one other text, Robillard and colleagues
(2013), found some support for the use of specific applications of gene therapy for human
enhancement reporting a 77% approval rate for the enhancement of normal memory function50.
Disease severity and availability of alternative treatments
Overall 20 studies examined opinions towards gene therapy to treat fatal or debilitating diseases
compared to minor physical conditions or benign conditions. Many found that disease severity
had a direct impact on acceptance of gene therapies for diseases such as incurable heart
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disease37, deformity34, neuromuscular diseases65, Schizophrenia40,54,58, Alzheimer’s50,51,62,
Parkinson’s41, and cancer29,31,43,48,53,54. More support was found for somatic therapy of fatal and
debilitating diseases over less severe diseases for adults35,40,55,62 and children55,62. Xiang et al.
found a large proportion of respondents were accepting of gene therapy for complex and
potentially severe diseases such as breast cancer (63.73%) and congenital heart disease
(60.28%). However, this proportion reduced with decreasing disease severity, falling to
44.38% for hypertension and 40.59% for attention deficit hyperactivity disorder (ADHD)53.
Similarly, 93% of respondents approved the use of gene therapy for Leber’s Congenital
Amaurosis, compared to 45% for ADHD51. Furthermore, Kim et al. (2006) found that within
their sample of participants with Parkinson’s disease, those who had milder symptoms seemed
to be more willing to participate in gene therapy research compared to those with more
debilitating symptoms41.
As the severity of the disease increased, so too did the acceptability of gene therapy. Evans
noted a 41% acceptability for a “death sentence” genetic defect39. Hendriks et al. found 85.2%
of individuals would accept somatic gene therapy for a serious disease, such as a neuromuscular
disorder, only decreasing to 66% when considering germline modification instead65. The same
was found for severity within a specific disease, with 52% of cardiac surgery patients willing
to enrol in a gene therapy trial for cardiovascular disease, and a further 33% if the heart disease
was otherwise incurable37. Liu et al. observed increased acceptability with severity through
comparison of early diagnosed cancer (63.1%) versus late stage cancer (85.1%)48, while
Uchiyama found support for therapies when the disease would either shorten life or result in
long-term care67. In contrast, van Lieshout and Dawson (2016) reported that adolescents were
more likely to be in favour of somatic gene therapy for minor (50%) in comparison to serious
diseases (36%)56.
Four studies evaluated gene therapy versus alternative treatments32,36,39,54. In a cohort of 16
cystic fibrosis patients, all indicated that they had a preference for gene therapy as an alternative
therapy over conventional heart and lung transplantation32. Holm found that oncology staff
deemed gene therapy (48.9%) to be a safer cancer treatment option than chemotherapy (7%),
with patients (26.7%) also agreeing gene therapy was safer than chemotherapy (6.7%, with
66.7% neutral)36.
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Somatic cell gene transfer versus germline transgenesis
Seventeen papers compared the attitudes of participants towards somatic cell gene transfer,
germline transgenesis or embryonic editing as three modes of therapeutic
intervention30,31,34,35,38,40,45,49,55,56,58,60,62,64-67. There was a noteworthy difference in the
acceptability of somatic gene therapy, and its benefits were largely accepted (range: 45%34 -
98% acceptance66). In contrast, the use of germline transgenesis was more divisive, with many
papers reporting participant wariness toward this type of therapy, resulting in a lower level of
acceptability34,35,38,40,45,49,56,58,62,64,65 (range: 16%34 - 71%35).
Exceptions to the view of somatic transgenesis being more favourable were Macer et al., who
only found a small difference in acceptability31; and both Scheufele and McCaughey who
reported similar levels of support for both somatic and germline therapies55,60. Iredale et al.
noted differences in the willingness to personally use gene therapy for somatic (95.5%) over
germline transgenesis (54.4%)38. This same cohort was divided when comparing the ethical
differences between the two modes of therapy, with 40.9% expressing that there is no ethical
disparity between somatic and germline gene therapy and 36.4% stating that the two therapies
are distinct.
Mode of delivery and assessment
Overall, four studies examined perceptions towards either the mode of gene therapy delivery
or how effectiveness would be assessed32,37,44,61. Cardiac surgery patients expressed a
preference for catheter-based delivery of a gene therapy product over surgical gene transfer
(94% vs 80% respectively)37. In that same study, adenovirus was considered an acceptable gene
transfer vector by 73% of patients, although the study did not assess the acceptability of other
types of gene vectors37. Haemophilia patients clearly had a preference for subcutaneous
administration (76.3%), with intramuscular and intravenous routes also considered positive
alternatives (66.2% and 60.1% respectively)44. Bone marrow transplantation was the least
favored administration modality, with 66.4% of patients declaring this method ‘not
acceptable’44. Individuals with sickle cell disease indicated increased apprehension upon
discovery that chemotherapy would be used prior to the infusion of stem cells that had been
treated with a modified HIV vector containing the therapeutic 𝛽-globin gene. This
apprehension was due to both the chemotherapy and resultant side effects, and also with the
use of the HIV vector as the delivery vehicle for transfer of the therapeutic gene, with
individuals describing its use as ‘scary’61.
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A single study analysed acceptability and assessment of gene therapy efficacy. This study used
a single nasal application of DNA-liposomes in cystic fibrosis patients and noted that nine of
the sixteen participants found the invasive nasal brushings, biopsies, or daily potential
difference measurements to be tedious and unpleasant. These methods of outcome assessment
subsequently had a direct negative bearing upon attitudes towards gene therapy32.
Risks of gene therapy versus the potential benefits of success
This theme examined the risks and benefits of treatments and balanced these with the likely
expectations that treatments would be successful. A total of 22 studies specifically examined a
range of risks and benefits18,19,29,31-33,41,43,44,47,49-51,53,54,57,59,61-63,65,67, and many noted that
acceptability of gene therapy or human genetic manipulation was very closely related to the
risk of the intervention50,62,65. In general, there was broad support for the benefits of gene
therapy for human use, however, potential risks were also important to consider. For example,
Robillard et al. (2014)51 found that 75% of a general sample of people from the USA thought
that gene therapy would have positive impacts on society, 74% agreed that gene therapy would
possibly provide cures for many diseases, and 54% thought that the benefits of gene therapy
outweigh any harms. In a large European Union survey, Hudson and Orviska (2011)47 found
that the majority of participants thought gene therapy was useful to society, however they also
had risk-related concerns. Gaskell et al. (2017) examined the public’s view of gene editing,
with 75% of respondents giving a positive evaluation of gene editing technology for adult
therapy. Participants frequently thought gene editing would lead to “improvements to quality
of life”; it would enable “curing dementia”; and that the “benefits outweigh[ed] the risks”57.
When participants identified risks they included unacceptable health risks65 and the possibility
of “things going wrong” due to mistakes such as the production of leukaemia in SCID trials47,
or potential negative future consequences61. For example, in a study of patients with sickle cell
disease, participants indicated that the risk of developing cancer following gene therapy meant
they would be trading sickle cell for a potentially more serious disease61. Although their disease
might impact their life and reduce their life expectancy, many thought it was better to continue
their current treatment rather than risk developing a life-threatening condition. Others
identified the risk of deliberate human germline alterations that would impact future
generations47. Together these results suggest that it is important to understand the level of such
off-target effects that participants would find acceptable for each disease65.
15
Furthermore, some participants voiced disapproval that gene therapy was unnatural31,43, with
others saying diseases have a purpose in life65. In a German study, Hampel et al. (2000) found
that only one third of the people they interviewed thought that the risks of genetic engineering
outweighed the chances of success18. In addition, over half of the pre-service teachers in one
study either agreed or strongly agreed that “changing a person’s genes is too risky, whatever
the benefit might be”54. However, these feelings were countered in an earlier gene therapy trial
reported by Blair et al. (1998), which stated that participants generally assumed that “doctors
would not put them at risk”32. Furthermore, in a Chinese sample 41% of respondents disagreed
with the statement “It is too risky to try to change people’s genes” and 41% were neutral
(remainder unknown)53. The willingness of participants to take part in a gene therapy trial also
appeared to be related to their risk perception, with those that were more willing to participate
also more optimistic about the potential benefits of gene therapy41.
In a cystic fibrosis gene therapy safety trial using liposomes for delivery—where the vector is
regarded as being safer than viral vectors—almost all patients thought that they had placed
themselves at no risk whatsoever by taking part32, albeit this was prior to the SCID trials that
identified the risks of genotoxity. In contrast, although cancer induction is a minor risk for gene
therapy, more than half of a group of patients with haemophilia thought that the long-term
perceived risk of cancer development was a major concern44. Kim et al. (2006) also found that
participants that were willing to participate in gene therapy trials for Parkinson disease
perceived less risk than those not willing to participate and were also more optimistic about the
benefits to society41.
Demographics
The interdependent relationship between risk and acceptability also varies based on
demographic factors. Hampel et al. noted that men were more accepting of gene therapy, and
perceived fewer risk than women18. In another study, women were significantly more likely to
agree with the statement ‘‘It is too risky to try to change people’s genes’’53 while men were
found to have higher levels of confidence in safety47.
Risk perceptions did not vary greatly with ethnicity with the exception of one Chinese survey,
which found that only 31% of respondents agreed with the statement that “The benefits of gene
therapy will be greater than the harm it may cause”53. However, the authors did note that the
greater concern of the Chinese population about gene therapy may be caused by an absence of
understanding and media coverage in China53.
16
Potential ethical or moral issues
The application of genome engineering requires significant ethical and moral consideration and
this was a primary theme across over half of the included papers, with 24 articles discussing
these issues when determining levels of acceptability19,29,31,32,34-36,38,39,43,45-47,49-51,53,56-
58,60,62,64,65. The most common ethical concern was that genetic modification was interfering
with nature (unnatural)29,31,32,38,45,46,49,50,53,62,65 and that it was “playing God”29,31,36,46, although
some religious leaders considered it “preservation and advancement of life”46. As expected,
gene therapy for diseases was found to be significantly more morally acceptable compared to
enhancement35,38,39,50,51,57,60,62,64. Slovenian students considered somatic gene therapy as
ranking highly in terms of usefulness and moral acceptability45,49. As previously discussed, the
acceptability of germline transgenesis is generally lower, with the potential for inadvertent
germline transmission demonstrated to be of ethical concern50.
Some of the moral concerns at a societal level include the impacts of increased longevity51, the
accompanying exponential population growth resulting from the decreased incidence of
disease51,53, and the potential for uneven distribution of resources50. Further ethical
considerations were related to the reduction in human diversity56,65 and the lack of natural
selection43,56. Techniques that are perceived as substantially less risky are considered more
‘morally acceptable’ and ‘useful to society’47,49. Further moral considerations included the
perception that natural abilities would not be unique if people use gene therapy for
enhancements56 and may even threaten the integrity of the human species34,56. There could also
be a risk of losing a sense of self (personal identity), particularly in the context of gene therapy
for the brain, or changes in sexual orientation as a result of gene therapy50,51. In contrast, those
not opposed to germline transgenesis for improved intelligence cited that it would allow users
to contribute more to society, and they had concerns of falling behind if others instigated its
use first65.
A significant recurring ethical concern was whether a parent has the right to decide on the use
of gene therapy, either somatic or germline, for their child. Some studies suggested that parents
had no right to modify their unborn child’s genes using germline therapy44,49,56,65, while others
discussed the treatment of children as a parental right or duty38,57, or even a moral imperative
towards one’s offspring by not withholding the opportunity for therapy and subsequent
improvement in quality of life65. Ninety-nine percent of respondents thought it was ethically
sound to administer a gene therapy for cystic fibrosis to children (aged 6 months to 17 years),
on the condition that safety was the priority19. The administration of gene therapy in utero or
17
to a child for a fatal or debilitating disease also scored highly by the public, indicating general
agreement of these uses62. Five other studies were in agreement with using gene therapy on
children29,31,34,38,43, with two showing more support for gene therapy in children than adults29,31.
Several studies showed support for in utero gene therapy for health-related reasons that would
not result in germline transgenesis34,40, ones that would result in germline modification55,65, or
ones that were embryonic but did not specify germline transgenesis30,64,66.
In some instances, the ethical division was less clear with 61% of individuals in agreement that
parents could use human germline genome editing for the purpose of having a child if there
was no other means to do so. This decreased to 45% when used to reduce the risk of a serious
disease as opposed to being a treatment for it58. Iredale et al. found support for the statement
that parents have the right to obtain gene therapy for their children (73%), but less support for
in utero gene therapy where 55% agreed with the statement that “children had the right to be
born with the genetic make-up they had at conception”, while 27% were in disagreement, and
18% felt unsure38.
Another interesting topic of ethical debate was the selection of participants that would be
enrolled in gene therapy trials46,51 and the ethical responsibility to ensure accurate information
for consent when participating in high-risk research46,51. Participants in various studies also
determined that gene therapy had the scope for generating genetic discrimination and
injustice50,53. The high cost of gene therapies was cited as a concern53,62 with the associated
ethical apprehension being the creation of different classes of individuals based on who could
afford gene therapy for modification purposes51, or therapy being a privilege only for the
wealthy and powerful53.
When given the opportunity to discuss controversial scientific topics, such as gene editing,
communication with a panel of topic-specific experts was shown to have no impact on the level
of ethical concern for gene editing or the belief that this sort of therapeutic intervention would
progress humankind. Instead, such discussions were found to significantly affect the belief that
gene editing is morally acceptable, with agreement increasing following such panel
discussions59, a trend supported by others40.
Trust, fears, or concerns
A total of 21 studies raised the topic of trust, fears and concerns related to the use of gene
therapy or gene editing18,29,31,32,35-37,41,42,44,46,47,50,51,56,57,61-63,65,67. Most fears could be grouped
into medical or trial participation concerns. Concerns related specifically to medical outcomes
18
included infections32,41,44, cancer41,44,61, inflammation41, thrombosis44, bleeding41, infertility61,
fear of chemotherapy61, reactions to anesthesia41, and contracting hepatitis44 or HIV61. More
generally, participants expressed concern about misuse31, safety62, unacceptable health
outcomes29,31,47,65,67, adverse medical side-effects50,51,62, their current disease getting worse41,
or unknown or unpredictable long-term consequences such as undesirable
mutations32,37,41,50,56,57,63,65. The acceptability of additional treatment side effects has been
shown to correlate with the potential cure rate, highlighting a trade-off between side-
effect/therapeutic benefit of a gene therapy treatment36. Participants also had concerns over
being excluded from other clinical trials41, and racial and social disparity leading to recruitment
bias for clinical trials46. A lack of adequate information about gene therapy before a trial was
also cited as a worry50,51. Surprisingly, the fear of eugenics was only mentioned twice31,63 and
does not appear to be a significant cause for concern in those considering the application of
gene therapy.
Many fears and concerns were accompanied with an inherent lack of trust. These issues centred
around mistrust of research46, scientists18, the medical system46, and government rules and
those in charge42. Ng et al. determined that respondents were most trusting of international
regulatory bodies such as the World Health Organisation, for regulatory oversight while
scientific organisations and ethics committees were deemed less favourable35. Religious
organisations, trade unions, and political parties rated lower still in terms of trust, from a
regulatory perspective35. Scientists expressed issues of trust surrounding the control on
techniques to ensure protection from misuse29 leaving scope for change and improvement.
Changes over time
Although the gene therapy and gene editing fields have rapidly advanced over the last decade,
only two papers specifically looked at changes in attitudes towards gene therapy over time35,43.
Both reported on public attitudes to gene therapy in Japan based on opinion surveys. Macer et
al., covered surveys conducted from 1991 to 200343, finding that levels of optimism towards
gene therapy for a serious or fatal disease remained relatively consistent over that time period.
They also reported that there was little difference in attitudes towards gene therapy between
the public and scientists43. Ng et al. reported on a subset of the same surveys from 1991 to
200035.
19
Discussion
The purpose of this paper was to synthesise the research to date on people’s perceptions of
gene therapy and gene editing for human applications, and to highlight factors that influence
acceptability. Key points are summarised below along with a series of recommendations to
advance the work in this field.
Impact of demographic factors
Demographic factors are known to play a substantial role in influencing public perceptions
relating to genetic modification. Generally, younger individuals, males, those with lower
religiosity, better (self-reported) knowledge, and increased trust in scientists were shown to
have more support for both gene therapy and gene editing technologies. Specifically, most
studies found that younger participants were more accepting of gene therapy, possibly due to
an increase in concern by older individuals and reduced exposure to the development and use
of these modern technologies. Only a single study found that women were more accepting of
gene therapy than men62. One explanation for these gender-associated differences in
acceptability could be the concern that women have towards science and technology, and the
increasing control that technology has over our lives suggested by some researchers68. While
it has been shown that women are generally more risk averse than men69, it is possible that the
perceived risks of gene therapy may be more acceptable to women in certain situations, for
example, when confronted with the reality of a serious or debilitating disease affecting one's
offspring or children in general compared to gene therapy as a whole for adults. These
differences also call for improved gender-specific educational programs to address the specific
concerns more often associated with women.
Knowledge and education levels were generally significant predictors of the level of support
for these technologies, however some findings were mixed. While it has been suggested that
negative perceptions of gene therapy can be attributed to a lack of knowledge, the issue is more
complex. Mixed results regarding the relationship between knowledge and perceptions could
be due to the inconsistent way that knowledge is measured, for example through career choice
or education. Self-reported and tested knowledge on genetics were found to have the most
consistent results, however there remains a need for research to unify measurements of
knowledge for consistency, clarity, and comparative analyses. Strong et al. (2017) also suggests
that participant engagement over time might give opportunities to provide education;
answering questions, addressing misconceptions, and allowing participants to better weigh up
20
the risks and benefits of treatment61. They also recommend the use of education materials
containing a combination of visual and numerical information, along with patient
experiences61.
Perceptions based on treatment specifics
Overall, there was substantially less support for the use of gene therapy for non-medical (i.e.
enhancement) purposes compared to medical applications. Acceptance was lowest for non-
therapeutic enhancement procedures, driven strongly by concerns such as “playing God”,
“going against nature”, and also societal concerns such as disparities in resource allocation or
access to procedures based on socioeconomic standing that could lead to discrimination or
inequality. Gene therapy was also more acceptable for serious or fatal diseases rather than
debilitating diseases (e.g. Alzheimer’s or Parkinson’s). This is likely due to the perception that
gene therapy carries some risks, so the risk-benefit ratio is perceived to be inversely
proportional to the severity of the disease. For some participants, the health risks were
unacceptable due to the possibility of “things going wrong”, and that for patients with less
severe conditions it was better to continue their current treatment rather than risking
development of a life-threatening condition.
Importantly, in cases of disagreement for genetic modification for health-related applications,
an absence of a complete understanding of the technologies themselves and their
accompanying potential risks were cited as contributing to apprehension to their use as opposed
to the actual genetic modification itself30. Adequate education of participants about these
aspects will be of fundamental importance to its broader uptake and acceptance.
Acceptability was inversely related to the invasiveness of the delivery technique or assessment
of therapeutic efficacy, however, increased discomfort or side effects arising from a gene
therapy were considered acceptable for a fatal disease if there was potential for that therapy to
provide a cure. An important element of patient acceptability was the description of the mode
of gene delivery (i.e., the gene vector). Describing the delivery vehicle for transfer of the
therapeutic gene as an ‘HIV vector’ had a direct negative bearing upon attitudes towards gene
therapy61. It is possible that if it were instead described as a ‘lentiviral gene vector’, then it
would be less confronting, and lead to greater acceptability. However, it should be noted that
this level of technical detail and the implications of using these different vector delivery
methods may not be easily understandable by everyone. Education consisting of simple
21
explanations that clearly outline the points of differences between the vector delivery systems
may aid understanding to enable the public to accurately assess each therapy.
Risks versus benefits
The importance of scientists and medical personnel clearly explaining the possible risks and
benefits of genetic therapies is becoming more obvious. In many studies, knowledge of gene
therapy was intertwined with perceptions of its risks and benefits. For example, participants in
one study remarked that including the percentage likelihood of risks was helpful for them to
form their own opinions about gene therapy61. Willingness to take part in clinical trials was
also closely related to personal risk perceptions and optimism about the potential benefits.
Hudson and Orviska (2011) found that people who were more educated and had greater
knowledge about gene therapy viewed it as less risky47.
Jaffé et al. (2006) noted that they did not explicitly describe the risks of gene therapy in their
study, and that providing more information to participants may have resulted in them being
less accepting of risk19. In support of this notion, when the potential risks and side effects of a
gene therapy were explicitly explained to patients with sickle cell disease they perceived the
treatment less favourably61. Weisberg et al. (2017) also found that the support for human
germline modification was slightly lower when the risks were made more explicit63. However,
perceptions of risk and benefit are not necessarily inversely related59, highlighting the need for
open discussions with stakeholders for each application and therapy as they may have variable
risk profiles.
Trust, fears, concerns, and ethical and moral issues
Fear and concern stem mainly from the misuse of these technologies, unacceptable health
outcomes, adverse medical side-effects, a current disease getting worse, or unknown or
unpredictable long-term consequences such as undesirable mutations. For example participants
considered germline genetic modifications such as introducing HIV resistance “a slippery slope
toward other applications deemed morally unacceptable”65. These applications have recently
become a public focus due to the use of CRISPR by Chinese Scientist Dr. Jiankui He to alter
the genome of human embryos prior to implantation in order to confer HIV resistance in two
infants (November 2018). This news received swift international condemnation, with the
medical field saying it is irresponsible to proceed with clinical germline editing at present70.
This type of rogue research and media attention creates mistrust of research, scientists, the
medical system, government rules, and those in charge.
22
While there was little empirical research related to cost as a concern, anecdotally this topic is
rapidly becoming one of the most frequently mentioned aspects of the gene therapy debate in
public forums. As such, it is an important avenue for future research. Future research should
aim to compare actual real-world costs and people’s perceptions of costs for gene therapy
relative to alternative therapies. It would also be interesting to assess the influence of gene
therapy cost and payment models (e.g. public versus private health insurance and outcome-
versus value-based pricing) on people’s perceptions and acceptability.
For some people there are ongoing ethical and moral issues surrounding gene therapy and gene
editing. It is therefore a moral obligation of all those involved in the development and
implementation of therapeutic therapies, from scientists to policy makers to ensure that due
diligence is performed with regard to the safety of these therapies, and to ensure that complex
information is relayed in an understandable and transparent manner to regain trust and mitigate
these current fears and concerns. The issues of mistrust amongst particular populations,
especially some minority groups, also needs to be addressed as they form a barrier for the
recruitment of these groups into clinical trials46.
The complex relationship between the use of gene therapy and its moral and ethical
considerations should be at the forefront of all discussions involving genetic modification, with
personal, societal, and environmental implications balanced against the potential benefit of
genome modification. Continuous conversations between patients, the public, scientists,
clinicians, and policy makers need to be built and maintained to deliver resolutions /
agreements on how to move forward with these therapies and what would be considered "right"
at a particular point in time for the world's population.
Changes over time
More than half of the papers in this review were published in the last eight years, likely owing
to the maturity of the gene therapy field as a whole and also more media attention and
discussions around the topic with the public. This demonstrates the increasing focus that the
scientific community is placing on this type of work as a viable treatment option for a range of
different complex diseases, and the importance of understanding people’s perceptions towards
this technology. However, since 2007, none have looked at changes in perceptions over time.
Collectively, from the studies reviewed it appears there is an upward trend in acceptability of
gene therapy as a treatment alternative when looking at the percentage of people who were
accepting, particularly for medical purposes. Some views have also changed over time based
23
on other medical advances. For example, participants in 1999 viewed gene therapy for HIV as
acceptable if it could prolong lives33. In 2018 a different study reported that germline
modification to produce HIV resistance was not considered necessary due to the low risk of
acquiring HIV65, and the likely availability of other acceptable and effective treatments.
While the general trend for medical somatic therapy shows an increase in acceptability over
time, germline modifications remain contentious and a heated source of ethical debate.
Deviations from the status quo have been vehemently frowned upon with He Jiankui’s editing
of human embryos sparking international outcries71 that have culminated in the Chinese
government immediately tightening up regulations against germline editing72. Numerous cell
and gene therapy committees have rebuked the act and have subsequently called for an
international moratorium on the use of germline genetic modifications73. The expansion of gene
therapies into the medical arena, coupled with increased media exposure are likely to change
current perceptions. It will be critical to understand how the public’s perception is tracking
with these advancements and how much of an impact the recent gene therapy successes have
had on the public’s perception and willingness to participate in gene therapy clinical trials and
whether there are still additional barriers that need to be overcome in the future. Future research
could usefully track potential changes in perceptions over time via longitudinal methods, or by
examining current versus retrospective accounts of perceptions among different samples.
Limitations and future research directions
Limitations exist with all forms of research, and the research presented in this field is no
exception. In order to provide a comprehensive review, all relevant studies were included.
However, it was clear that a number of misconceptions surrounding gene therapy and gene
editing still exist, both among researchers and the public. For example, there were suggestions
it could change sexuality 50, demonstrating that some of the studies reviewed did not understand
the true purpose, capabilities, and/or reasonable applications of current gene therapy and gene
editing techniques. It is likely that these misconceptions are driven by the media and
sensationalised in movies (e.g., Gattaca). As such, it is essential for future research in this space
to be performed by multi-disciplinary teams of gene therapy experts—including clinical
researchers, basic scientists, social scientists, bioethicists and patient advocacy groups—to
ensure a comprehensive understanding of perceptions of gene therapy and gene editing.
Overall, the measurement of perceptions of gene therapy and gene editing was inconsistent and
there is a need for future research to employ standardised and validated forms of measurement
24
in order to draw firm conclusions. In addition, concepts such as “risk” with regard to gene
therapy have not been clearly defined within the literature, and as such, this term was used in
a variety of contexts. These included general non-specific risks57, actual risks posed by gene
therapy 65, negative consequences61, or greater philosophical risks pertaining to humankind34,56.
While the studies reviewed reported on data from a wide range of samples, relatively little
research has been done on specific consumer groups. Future research should address this by
examining the perceptions of individuals who are closely associated with different diseases.
Lastly, only two studies (that drew from the same data set) specifically reported on changes
over time 35,43. As such, any findings related to changes should be considered with caution.
Recommendations and future directions
Public engagement can improve knowledge and change risk and benefit perceptions, but the
relationship between these factors remains complex59. Based on the studies we reviewed, we
have created the following list of recommendations and directions for future research to
improve public perceptions of gene therapy.
1. Improve the standard of informed consent
Clear and consistent communication between patients, clinicians, and clinical trial managers is
integral to fostering a sense of trust and empowerment to patients choosing to undergo genetic
therapy. In particular, it is important to design informed consent documentation specifically for
gene therapies, being mindful of the phrasing of content, terminology, and the amount of detail
provided51,61. Information should be engaging with complex ideas preferably portrayed with
images and videos for clarity37. Specific attention should be given to accurately convey
messaging that is often portrayed fallaciously within the media (e.g,. the generation of eugenics
or designer babies). Future research should obtain insight from focus52 and patient advocacy
groups to determine any potential miscommunication of information prior to broader
dissemination.
2. Use minimally invasive procedures
While invasive procedures remain the only mode of delivery for many potential gene therapies,
technological advances are likely to bring about less invasive methods of delivery, and with
that an expected increase in acceptability. Given the direct negative correlation between
invasiveness and acceptability highlighted above32, there must be a continuing drive to provide
innovative ways to combat the current hurdles associated with non-invasive delivery of some
gene therapies when alternatives may be possible.
25
3. Develop greater trust
To gain public trust it is critical to deliver information to the public and potential patients that
is understandable, relatable, unambiguous, and reliable62,65. Greater emphasis needs to be given
to the development of public engagement tools for scientists and clinicians to feel adequately
equipped to engage with the public and build long-standing and honest relationships built on
trust. A recent 2019 study went so far as to note that sharing visuals of scientists themselves
versus innate lab objects was enough to change perceptions and garner increased trust by
humanising scientists on social media74.
Furthermore, information should be relayed frequently for the public to remain updated and
feel empowered by new developments with the gene and cell therapies46. It is important to
address any shortcomings in understanding or inaccuracies with reliable scientific content to
prevent negative perceptions towards genetic therapies based on misinformation46,61. It is likely
that increased exposure and a continuous track record of transparency between scientists and
the public would significantly improve issues of trust.
4. Develop appropriate policy frameworks for gene therapy regulation
Patients need to know that new therapies are being correctly regulated and that policy decision-
makers are provided with enough up-to-date scientific insight and public participation57 to
drive these therapies forward while keeping safety a priority. Pairing current expert knowledge
with a clear understanding of past errors has already provided improved guidelines for
regulating gene therapies, but there is still scope for international clarity and consensus for
many of their uses. Public confidence can be developed and maintained through instigation of
more dynamic and open communication between the regulatory agencies that are drafting
guidelines and implementing policies. This has become a realization with the recent notice by
the FDA requesting formal input into their draft guidelines for the enhancement of diversity of
clinical trial populations, enrolment practices, eligibility criteria, and trial designs75. This
method of consultation and transparency specifically for gene therapy is highly recommended
to improve the quality of the guidelines through constructive collective consultation and
improve public trust in health agencies. It will also be essential to include post-success analyses
in any future research looking at perceptions of somatic gene editing changes.
The implications of genetic modification are not always well understood or even known
scientifically, so we should continue to tread with caution while continuing to engage in global
discussions on what is defined as acceptable. There is an urgency to gain international
regulatory control over the use of these therapies for the right purposes, to avoid inappropriate
26
application of genetic therapies. Currently, this is largely regulated by the Food and Drug
Administration in the USA who are increasing the number of clinical reviewers for the
evaluation of cell and gene therapies, and the European Medicines Agency (EMA) Advanced
Therapy Medicinal Product (ATMP) who have recently completed their consultation period
(July 2019) for guidelines of cell and gene therapies. Ideally, inter-agency consultation and a
unified global regulatory framework should be established to streamline the regulatory process
and determine which applications are deemed ethically, morally, and scientifically safe and
acceptable for clinical use across geographical boundaries.
5. Provide better gene therapy education to the public and stakeholders
The rapidly changing biomedical landscape is demanding more in-depth science and
biotechnology teaching, even at high school level. This shift is driven by a need to improve
basic science and biotechnology knowledge54 and bioethical principles49 for teachers and
students. Gaps in knowledge should be addressed prior to subsequent delivery of information
to ensure good foundational science understanding56. Clinicians in relevant fields must stay up-
to-date with the most current and ground-breaking gene therapy research and practice spanning
oncology, ophthalmology, haemoglobinopathies, immunodeficiencies, and lysosomal storage
diseases. Furthermore, knowing the factors that can influence people’s perceptions will be
critical to assist clinicians to act as a bridging point between patients and those developing gene
therapies, and assist them to garner acceptance from patients for clinical trials.
There is an increased need and desire for the public to know more about these new and exciting
genetic therapies. Opportunities to instigate multidirectional communication between the
public, scientists, clinical staff, and policy decision-makers using public engagement events59
and social media50 will play a pivotal role in expanding public knowledge. Training in public
engagement is essential for all involved in the development and clinical administration of these
therapies.
New and innovative ways of making connections between stakeholders are essential. Recently,
the American Society of Gene and Cell Therapy debuted their patient education program to
educate and inform patients, families, and the public about genetic diseases, therapies, and
updates on clinical trials76. More of these initiatives must be developed in the coming years to
further encourage education. Emphasis needs to be placed on finding ways to communicate,
particularly with women, individuals in rural areas, older individuals, those with strong
religious tendencies, and those with less education to promote gene therapy literacy
competency. This will subsequently assist these groups to participate in fact-based discussions
27
on the topic, and ensure that correct information is given to those with varying levels of
understanding.
6. Each gene therapy application must be considered on its merits
Gene therapies cannot be placed under broad “blanket” regulations. It has become clear that
each application will need to be assessed on its own merits and ratio of risk-to-reward30,65.
Policies and regulations generated should also be based on individual circumstances (risk,
degree of disease severity, and medical versus enhancement), as therapies that exhibit lower
risk or are for severe diseases that would have higher reward, are likely to be more acceptable,
and have an easier road to clinical implementation. Each application will also need to establish
the level of risk would be acceptable for patients undergoing specific gene therapy treatments
in situations where acceptability is conditional (e.g., method of delivery, access to alternatives,
assessment of efficacy)65. While acceptability has notably improved for certain applications,
others still require significant ethical and legal consideration before translation toward the
clinic. Currently, germline modification is banned worldwide, and is largely not ethically
accepted. In our opinion, subsequent human germline editing should continue to be banned
until an ethical and regulatory framework has been established and agreed upon following
extensive and broad-ranging consultations with the public, scientists, clinicians, stakeholders
and policy decision-makers.
Acknowledgements
The study was supported by the Australian Cystic Fibrosis Research Trust. MD was supported
by a Robinson Research Institute Career Development Fellowship. The authors would also like
to acknowledge Nikki May who assisted with the original search design, Chloe Craig who
assisted with the article quality assessment, and A/Prof David Parsons for his valuable topic
insight and manuscript feedback.
Author Disclosure Statement
No competing financial interests exist.
28
Table 1: Summary of the themes and their association to acceptability of gene therapy.
Theme
Subtheme
Acceptability
References
Demographics
Greater
knowledge/education
n=24
Positive
n=15
18,29,31,35,40,47,49,51,54,55,60
,62-65
Neutral
n=7
33,39,43,48,52,53,66
Negative
n=2
42,67
Gender (women)
n=18
Positive
n=1
62
Neutral
n=3
30,48,66
Negative
n=14
18,34,39,42,45,47,49,53-
55,57,63-65
Religion
n=10
Positive
n=0
Neutral
n=2
48,53
Negative
n=8
18,39,46,47,51,55,60,64
Age (young)
n=9
Positive
n=4
47,55,63,64
Neutral
n=4
42,48,57,66
Negative
n=1
61
Disease status
n=2
Positive
n=0
Neutral
n=2
38,63
Negative
n=0
Treatment specifics
Medical over non-
medical
n=21
Positive
n=20
30,31,34,35,38-40,43,50,51,53-
55,57,58,60,62,64-66
Neutral
n=0
29
Negative
n=1
56
Increased disease severity
n=20
Positive
n=18
29,31,34,35,37,39,40,43,48,50,51
,53-55,58,62,65,67
Neutral
n=0
Negative
n=2
41,56
Gene therapy over
alternative treatments
n=4
Positive
n=2
32,36
Neutral
n=0
Negative
n=2
39,54
Somatic over germline
transgenesis
n=15
Positive
n=11
34,35,38,40,45,49,56,58,62,64,65
Neutral
n=4
30,31,55,60
Negative
n=0
Increased invasiveness of
delivery
n=2
Positive
n=0
Neutral
n=0
Negative
n=2
32,61
Risks of gene therapy
Too risky
(risk outweighs benefit)
n=22
Positive
n=9
29,31,44,47,49,54,61,63,65
Mixed (balance of risk-
benefit)
n=5
33,50,51,59,62
Negative
n=8
18,19,32,41,43,53,57,67
Potential ethical or moral
issues
Effect of ethical and
moral issues
n=24
Positive
n=2
40,59
Mixed
n=4
45,46,49,65
Neutral
n=0
30
Negative
n=18
29,31,32,34,36,38,43,45-47,49-
51,53,56,62,64,65
Trust, fears, or concerns
Trust (lack of), fears, or
concerns
n=21
Positive
n=0
Neutral
n=0
Negative
n=21
18,29,31,32,35-
37,41,42,44,46,47,50,51,56,57,61
-63,65,67
Changes over time
Increase in time
n=2
Positive
n=2
35,43
Neutral
n=0
Negative
n=0
31
References
1. Dunbar, C.E., et al. Gene therapy comes of age. Science 359(2018).
2. Maeder, M.L. & Gersbach, C.A. Genome-editing Technologies for Gene and Cell
Therapy. Molecular Therapy 24, 430-446 (2016).
3. Aiuti, A., Roncarolo, M.G. & Naldini, L. Gene therapy for ADA‐SCID, the first
marketing approval of an ex vivo gene therapy in Europe: paving the road for the next
generation of advanced therapy medicinal products. EMBO Molecular Medicine 9, 737-
740 (2017).
4. Nienhuis, A.W., Nathwani, A.C. & Davidoff, A.M. Gene Therapy for Hemophilia.
Molecular Therapy 25, 1163-1167 (2017).
5. Morris, E.C., et al. Gene therapy for Wiskott-Aldrich syndrome in a severely affected
adult. Blood 130, 1327-1335 (2017).
6. Rosenberg, J.B., Kaminsky, S.M., Aubourg, P., Crystal, R.G. & Sondhi, D. Gene
therapy for metachromatic leukodystrophy. Journal of Neuroscience Research 94,
1169-1179 (2016).
7. Mendell, J.R., et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular
Atrophy. N Engl J Med 377, 1713-1722 (2017).
8. Alton, E., et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with
cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet
Respir Med 3, 684-691 (2015).
9. Cmielewski, P., Donnelley, M. & Parsons, D.W. Long-term therapeutic and reporter
gene expression in lentiviral vector treated cystic fibrosis mice. J Gene Med 16, 291-
299 (2014).
10. Senior, M. After Glybera's withdrawal, what's next for gene therapy? Nat biotechnol
35, 491-492 (2017).
11. Salzman, R., et al. Addressing the Value of Gene Therapy and Enhancing Patient
Access to Transformative Treatments. Mol Ther 26, 2717-2726 (2018).
12. Ohmori, T., et al. CRISPR/Cas9-mediated genome editing via postnatal administration
of AAV vector cures haemophilia B mice. Sci Rep 7, 4159 (2017).
13. Ramaswamy, S., et al. Autologous and Heterologous Cell Therapy for Hemophilia B
toward Functional Restoration of Factor IX. Cell Reports 23, 1565-1580 (2018).
14. Jung, I.Y. & Lee, J. Unleashing the Therapeutic Potential of CAR-T Cell Therapy
Using Gene-Editing Technologies. Mol Cells 41, 717-723 (2018).
15. Dai, W.-J., et al. CRISPR-Cas9 for in vivo Gene Therapy: Promise and Hurdles.
Molecular Therapy - Nucleic Acids 5(2016).
16. Hacein-Bey-Abina, S., et al. Insertional oncogenesis in 4 patients after retrovirus-
mediated gene therapy of SCID-X1. J Clin Invest 118, 3132-3142 (2008).
17. Howe, S.J., et al. Insertional mutagenesis combined with acquired somatic mutations
causes leukemogenesis following gene therapy of SCID-X1 patients. J Clin Invest 118,
3143-3150 (2008).
18. Hampel, J., Pfenning, U. & Peters, H.P. Attitudes towards genetic engineering. New
Genetics and Society 19, 233-249 (2000).
19. Jaffé, A., Prasad, S.A., Larcher, V. & Hart, S. Gene therapy for children with cystic
fibrosis - Who has the right to choose? J Med Ethics 32, 361-364 (2006).
20. Miller, H.I. Germline gene therapy: We're ready. Science 348, 1325-1325 (2015).
32
21. Cyranoski, D. Ethics of embryo editing divides scientists. Nature 519, 272 (2015).
22. Robillard, J.M. Communicating in context: a priority for gene therapy researchers.
Expert Opin Biol Ther 15, 315-318 (2015).
23. Macer, D.R.J., Azariah, J. & Srinives, P. Attitudes to biotechnology in Asia.
International Journal of Biotechnology 2, 313-332 (2000).
24. Schmidt, M. The Future of Public Perception of Gene Therapy in Europe, an Educated
Guess. in Gene Therapy: Prospective Technology assessment in its societal context
229-248 (2006).
25. Blendon, R.J., Gorski, M.T. & Benson, J.M. The Public and the Gene-Editing
Revolution. The New England journal of medicine 374, 1406-1411 (2016).
26. Moher, D., Liberati, A., Tetzlaff, J. & Altman, D.G. Preferred Reporting Items for
Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Medicine 6,
e1000097 (2009).
27. Kmet, L., Lee, R. & Cook, L. Standard Quality Assessment Criteria for Evaluating
Primary Research Papers from a Variety of Fields, (Alberta Heritage Foundation for
Medical Research, Edmonton, 2004).
28. Long, A.F. & Godfrey, M. An evaluation tool to assess the quality of qualitative
research studies. International Journal of Social Research Methodology 7, 181-196
(2004).
29. Macer, D.R. Public acceptance of human gene therapy and perceptions of human
genetic manipulation. Hum Gene Ther 3, 511-518 (1992).
30. McCaughey, T., et al. A Need for Better Understanding Is the Major Determinant for
Public Perceptions of Human Gene Editing. Hum Gene Ther 30, 36-43 (2019).
31. Macer, D.R., et al. International perceptions and approval of gene therapy. Hum Gene
Ther 6, 791-803 (1995).
32. Blair, C., Kacser, E. & Porteous, D. Gene therapy for cystic fibrosis: A psychosocial
study of trial participants. Gene Ther 5, 218-222 (1998).
33. Chen, S.Y. & Raffan, J. Biotechnology: Student's knowledge and attitudes in the UK
and Taiwan. Journal of Biological Education 34, 17-23 (1999).
34. Napolitano, C.L. & Ogunseitan, O.A. Gender differences in the perception of genetic
engineering applied to human reproduction. Social Indicators Research 46, 191-204
(1999).
35. Ng, M.A.C., Takeda, C., Watanabe, T. & Macer, D. Attitudes of the public and
scientists to biotechnology in Japan at the start of 2000. Eubios journal of Asian and
international bioethics : EJAIB 10, 106-113 (2000).
36. Holm, S. & Jayson, G. What do patients, their relatives and medical staff know about
genetic therapy? Bull Med Ethics, 13-19 (2001).
37. Bonatti, J., et al. Acceptance of gene therapy by the heart surgery patient. European
journal of cardio-thoracic surgery : official journal of the European Association for
Cardio-thoracic Surgery 21, 981-986 (2002).
38. Iredale, R., Dolan, G., McDonald, K. & Kirk, M. Public attitudes to human gene
therapy: a pilot study in Wales. Community Genet 6, 139-146 (2003).
39. Evans, M.D.R., Kelley, J. & Zanjani, E.D. The ethics of gene therapy and abortion:
public opinion. Fetal diagnosis and therapy 20, 223-234 (2005).
40. Sturgis, P., Cooper, H. & Fife-Schaw, C. Attitudes to biotechnology: estimating the
opinions of a better-informed public. New genetics and society 24, 31-56 (2005).
41. Kim, S.Y.H., et al. Volunteering for early phase gene transfer research in Parkinson
disease. Neurology 66, 1010-1015 (2006).
33
42. Barnett, J., Cooper, H. & Senior, V. Belief in public efficacy, trust, and attitudes toward
modern genetic science. Risk analysis : an official publication of the Society for Risk
Analysis 27, 921-933 (2007).
43. Macer, D., Okada, Y., Nakagawa, M., Chen Ng, M.A. & Inaba, M. Changing hopes
and concerns about gene therapy in Japan. Journal of Commercial Biotechnology 13,
209-222 (2007).
44. Costea, I., Isasi, R., Knoppers, B.M. & Lillicrap, D. Haemophilia gene therapy: The
patients'perspective. Haemophilia 15, 1159-1161 (2009).
45. Crne-Hladnik, H., Peklaj, C., Kosmelj, K., Hladnik, A. & Javornik, B. Assessment of
Slovene secondary school students' attitudes to biotechnology in terms of usefulness,
moral acceptability and risk perception. Public Underst Sci 18, 747-758 (2009).
46. King, W.D., et al. Pilot assessment of HIV gene therapy-hematopoietic stem cell
clinical trial acceptability among minority patients and their advisors. J Natl Med Assoc
102, 1123-1128 (2010).
47. Hudson, J. & Orviska, M. European attitudes to gene therapy and pharmacogenetics.
Drug Discov Today 16, 843-847 (2011).
48. Liu, Z.-m., Liu, C., Li, J.-y., Yu, C.-h. & Jiang, Y. The attitude of oncology physicians
and nurses to the acceptance of new drugs for gene therapy. Journal of cancer education
: the official journal of the American Association for Cancer Education 26, 248-253
(2011).
49. Črne-Hladnik, H., Hladnik, A., Javornik, B., Košmelj, K. & Peklaj, C. Is Judgement of
Biotechnological Ethical Aspects Related to High School Students' Knowledge?
International Journal of Science Education 34, 1277-1296 (2012).
50. Robillard, J.M., et al. Utilizing social media to study information-seeking and ethical
issues in gene therapy. J Med Internet Res 15, e44 (2013).
51. Robillard, J.M., Roskams-Edris, D., Kuzeljevic, B. & Illes, J. Prevailing public
perceptions of the ethics of gene therapy. Hum Gene Ther 25, 740-746 (2014).
52. Ganne, P., Garrioch, R. & Votruba, M. Perceptions and understanding of genetics and
genetic eye disease and attitudes to genetic testing and gene therapy in a primary eye
care setting. Ophthalmic Genet 36, 50-57 (2015).
53. Xiang, L., et al. Survey of Attitudes and Ethical Concerns Related to Gene Therapy
Among Medical Students and Postgraduates in China. Hum Gene Ther 26, 841-849
(2015).
54. Cebesoy, Ü.B. & Öztekin, C. Relationships among Turkish pre-service science
teachers’ genetics literacy levels and their attitudes towards issues in genetics literacy.
Journal of Baltic Science Education 15, 159-172 (2016).
55. McCaughey, T., et al. A global social media survey of attitudes to human genome
editing. Cell Stem Cell 18, 569-572 (2016).
56. van Lieshout, E. & Dawson, V. Knowledge of, and Attitudes Towards Health-related
Biotechnology Applications Amongst Australian Year 10 High School Students.
Journal of Biological Education 50, 329-344 (2016).
57. Gaskell, G., et al. Public views on gene editing and its uses. Nat biotechnol 35, 1022-
1023 (2017).
58. Musunuru, K., Lagor, W.R. & Miano, J.M. What Do We Really Think About Human
Germline Genome Editing, and What Does It Mean for Medicine? Circ.-Cardiovasc.
Genet. 10, 3 (2017).
59. Rose, K.M., Korzekwa, K., Brossard, D., Scheufele, D.A. & Heisler, L. Engaging the
Public at a Science Festival: Findings From a Panel on Human Gene Editing. Science
Communication 39, 250-277 (2017).
34
60. Scheufele, D.A., et al. U.S. attitudes on human genome editing. Science 357, 553-554
(2017).
61. Strong, H., et al. Patient Perspectives on Gene Transfer Therapy for Sickle Cell
Disease. Adv Ther 34, 2007-2021 (2017).
62. Wang, J.H., et al. Public Attitudes toward Gene Therapy in China. Molecular Therapy
- Methods and Clinical Development 6, 40-42 (2017).
63. Weisberg, S.M., Badgio, D. & Chatterjee, A. A CRISPR New World: Attitudes in the
Public toward Innovations in Human Genetic Modification. Frontiers in Public Health
5, 9 (2017).
64. Critchley, C., et al. Predicting Public Attitudes Toward Gene Editing of Germlines: The
Impact of Moral and Hereditary Concern in Human and Animal Applications. Front
Genet 9, 704 (2018).
65. Hendriks, S., Giesbertz, N.A.A., Bredenoord, A.L. & Repping, S. Reasons for being in
favour of or against genome modification: a survey of the Dutch general public. Human
Reproduction Open 2018(2018).
66. Treleaven, T. & Tuch, B.E. Australian Public Attitudes on Gene Editing of the Human
Embryo. J Law Med 26, 204-207 (2018).
67. Uchiyama, M., Nagai, A. & Muto, K. Survey on the perception of germline genome
editing among the general public in Japan. Journal of Human Genetics 63, 745-748
(2018).
68. Hornig, S. Gender Differences in Responses to News about Science and Technology.
Science, Technology, & Human Values 17, 532-542 (2016).
69. Shurchkov, O. & Eckel, C.C. Gender Differences in Behavioral Traits and Labor
Market Outcomes. in The Oxford Handbook of Women and the Economy (2017).
70. Buning, H., et al. Consensus Statement of European Societies of Gene and Cell Therapy
on the Reported Birth of Genome-Edited Babies in China. Hum Gene Ther 29, 1337-
1338 (2018).
71. Cyranoski, D. & Ledford, H. Genome-edited baby claim provokes international outcry.
Nature 563, 607-608 (2018).
72. Cyranoski, D. China set to introduce gene-editing regulation following CRISPR-baby
furore. Nature (2019).
73. Lander, E.S., et al. Adopt a moratorium on heritable genome editing. Nature 567, 165-
168 (2019).
74. Jarreau, P.B., et al. Using selfies to challenge public stereotypes of scientists. PLoS
ONE 14, e0216625 (2019).
75. Enhancing the Diversity of Clinical Trial Populations-Eligibility Criteria, Enrollment
Practices, and Trial Designs; Draft Guidance for Industry; Availability. Vol. 84 (ed.
Services, D.o.H.a.H.) 26687-26688 (2019).
76. American Society of Gene & Cell Therapy (ASGCT) Patient Education Program.
(2019).
