If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
The treatment of inherited metabolic disorders (IMDs) has traditionally relied on dietary interventions that are difficult to maintain, expensive, and socially isolating. The development of gene therapy for IMDs aims to provide sufficient gene activity to address the underlying causes of these conditions. This study surveyed health care providers (HCPs) to characterize their familiarity with gene therapy technologies and to identify educational needs across roles in a multidisciplinary care team.
The link to a Web-based, 26-question survey was distributed to HCPs in North America and Europe who were involved in IMD patient care. Results were analyzed using descriptive statistics.
Of the 590 survey link recipients, 64 completed the survey. Of these, 35 (55%) respondents were physicians, 23 (36%) were dietitians, 3 (5%) were nurse practitioners, 2 (3%) were genetic counselors, and 1 (2%) was a nurse. Most survey respondents (88% [n = 56 of 64]) reported the belief that gene therapy for IMDs would be available within 5 years of study conduct. Although nearly all physicians (97% [n = 34 of 35]) expressed awareness of gene therapy, rates of reported familiarity were lower among dietitians (57% [n = 13 of 23]); confidence in conversations with colleagues and patients/caregivers was also discordant. Nearly all HCPs wanted education on gene therapy advancements, and the most preferred informational sources were published literature and congress presentations.
There is an urgent need for education on topics related to gene therapy modalities. Professional education on gene therapies is desired across all specialties and will be important for unified treatment practices in IMD care.
Multiple therapeutic modalities differentially target the underlying pathology of individual IMDs, leading to the development of options such as enzyme replacement therapy, chaperone therapy, modulation of the microbiome, and organ transplantation, among others.
Organ transplantation can ameliorate or cure disease, as it introduces a normal gene for the defective enzyme in an appropriate organ, at the cost of introducing new transplant-related medical risks, including graft failure, graft rejection, immunosuppression, surgical complications, and even death.
Pegvaliase, a subcutaneously injected enzyme substitution therapy allowing alternative metabolism of blood Phe, has been shown to reduce blood Phe concentrations in patients with PKU in Phase III clinical trials and in real-world settings.
Although gene therapy has been under investigation for at least 25 years, it is unclear how well understood the modality is among multidisciplinary care management teams that typically care for patients with IMDs and include health care providers (HCPs) in distinct roles with specialized knowledge regarding patient care, support, and education.
As clinical trials and approvals for gene therapy of IMDs advance, it is important to identify and address knowledge gaps for all members of these teams to allow a cohesive therapeutic approach. To that end, we performed a survey to characterize the educational needs associated with gene therapy among physicians, dietitians, nurses, nurse practitioners, and genetic counselors who currently treat patients with IMDs.
Participants and Methods
We developed a Web-based, 26-question survey with multiple-choice and free-text responses. The survey recorded the demographic characteristics of survey respondents, including HCP role, medical specialty, years in practice, practice location, and how many patients with IMDs were under their care. The survey also recorded responses regarding disposition toward gene therapy research, research considerations during the coronavirus disease 2019 (COVID-19) pandemic, and the respondent's educational preferences. In addition, respondents were asked to rank 8 outcomes as the strongest indicators of success in gene therapy research. Free-text answers were collected on indicators of success in gene therapy research, preferred sources of data and/or information about gene therapy research, and educational needs or interests associated with gene therapy research. Questions related to awareness or familiarity with gene therapy research were scored on a 4-point Likert scale ranging from “not confident” to “very confident.” A response option of “not relevant to my practice” was offered for questions related to awareness of or familiarity with gene therapy research, given the various HCP types that may have responded to the survey. Although this research was exempt from Internal Review Board approval due to the nature of the survey, the sponsor's medical, regulatory, and legal review teams evaluated the methodology and ensured ethical conduct of the study. The survey is reprinted in the Supplemental Appendix. Survey Text of this report (see the online version at doi:10.1016/j.clinthera.2022.07.002).
Survey Sampling and Data Collection
The Website link to this survey was distributed to members of the Society for Inherited Metabolic Disorders, Genetic Metabolic Dietitians International, and a global listserv of metabolic nutritionists. The survey was available for responses from July 16, 2020, through November 30, 2020. Respondents who declared they were not involved in the management of patients with IMDs were deemed ineligible, and the survey was automatically terminated. All responses should be considered self-reported in the absence of external validation.
Responses to survey items that were categorical variables were evaluated with descriptive statistics (ie, frequencies). Responses from incomplete surveys were discarded. A survey was deemed incomplete if: (1) the respondent terminated the survey prematurely (ie, without answering all of the questions); or (2) the respondent did not qualify for the survey because he or she did not manage patients with IMDs or practiced in a geographic region outside of North America or Europe.
Sample Demographic Characteristics
Links to the Web-based survey platform were sent via e-mail to 590 clinicians caring for patients with IMDs, including physicians, nurses, nurse practitioners, and dietitians. A total of 132 persons initiated the survey, generating a response rate of 22.4%. There were 64 completed responses, forming the respondent population (Table I). The majority of respondents practiced in the United States, most participants self-reported their expertise as “expert” or “competent” in the management of IMDs, and 80% (n = 51 of 64) cared for both pediatric and adult patients. Respondents reported they had practiced for an average of 16.7 years (range, 2-49 years).
Table IDemographic characteristics of survey respondents.
Survey Respondents (N = 64)
Practice location, no. (%)
Country within the European Union
Time in practice, mean (range), y
16.7 (2–49; n = 63)
Self-reported expertise, no. (%)
Expert/manage a high volume of patients
Competent or proficient/manage a moderate volume of patients
Novice or new to the field/manage a low volume of patients
Role in patient care, no. (%)
No. of patients with IMDs seen in practice each year, mean (range)
Total patients with IMDs
No. of respondents: 63 331 (0–2000)
Patients aged 0–2 y
No. of respondents: 61 46 (0–500)
Patients aged 2–12 y
No. of respondents: 61 113 (0–700)
Patients aged 12–16 y
No. of respondents: 60 59 (0–500)
Patients aged ≥16 y
No. of respondents: 60 108 (0–500)
Research participation, no. (%)
IMD-related research in humans
IMD-related research in preclinical settings
IMD-related research in both clinical and preclinical settings
Overall, 39 respondents (61%) were actively involved in IMD-related research at the time of the survey, including 28 physicians, 8 dietitians, 2 nurse practitioners, and 1 nurse. Of these researchers, 56% (n = 22) were involved specifically in gene therapy research (16 physicians, 4 dietitians, 1 nurse practitioner, and 1 nurse).
Respondent Views on Gene Therapy Research
A large majority of respondents (88% [n = 56 of 64]) thought that there would be gene therapy options for IMDs available within 5 years from the conduct of the study. Of the 8 respondents who did not agree with that statement, 6 said the modality is unlikely to be available within that time frame, 3 said that the cost would be a deterrent, 4 were uncertain of the efficacy of gene therapy, and 3 expressed concerns about the durability of the treatment effect.
Respondents ranked a provided list of efficacy indicators for gene therapy to indicate their expectation of potential outcome success (see Supplemental Table I in the online version at doi:10.1016/j.clinthera.2022.07.002). The responses receiving the highest rankings for the strongest and second strongest indicators of potential success were “absence or mitigation of chronic symptoms” (23% and 17%, respectively), “absence or meaningful decrease in emergency department visits or hospital admissions” (19% and 21%, respectively), and “normal or meaningful improvement in neurocognitive/neuropsychological function for relevant IMDs” (21% and 12%, respectively). Respondents answered a free-text request for other potential indicators of success with respect to safety outcomes (eg, “minimal adverse events,” “no rejection or decrease in efficacy”), efficacy outcomes (eg, “long-term efficacy/outcomes,” “neurological and mental health improvements”), financial impact (eg, “reduced net cost per decade of life” for families and public health systems), and other measures of disease burden (eg, biomarkers, improved compliance).
Respondents expressed moderate concern that the COVID-19 pandemic could potentially have a negative effect on gene therapy research, including increasing patient fears of gene therapy with a viral vector (76% [n = 42 of 55]), that the use of an immunosuppressant regimen during the pandemic could increase a patient's risk of contracting COVID-19 (76% [n = 42 of 55]), or that there could be an interaction between the novel coronavirus and adeno-associated virus (AAV) vectors used for some gene therapies (56% [n = 31 of 55]). Among the free-text answers provided by the respondents were concerns about fewer in-person physical examinations, delays or interruptions to research during shutdowns, travel restrictions, availability of clinical researchers, risk of infection, and the cost burdens on health care systems and budgets.
Respondents’ Present Knowledge of and Comfort With Clinical Conversations About Gene Therapy
Most respondents (81% [n = 51 of 63]) expressed awareness of gene transfer with viral vectors but were less familiar with other gene therapy technologies; 7 respondents were not familiar with any gene therapy technologies. Nearly all physicians (97% [n = 34 of 35]) and most dietitians (57% [n = 13 of 23]) expressed awareness of or familiarity with gene transfer with viral vector technologies.
Respondents reported they had frequent discussions about gene therapy within their practices (Figure 1). More than one third reported they responded to patient or caregiver queries about gene therapy technology once or a few times, and 20% reported having such conversations every few weeks. Conversations to address questions from other HCP colleagues occurred with similar frequency: 16% and 9% of respondents reported having such conversations with patients/caregivers or HCP colleagues, respectively, every few days.
Subset analysis by HCP role in IMD care identified differences in the familiarity with gene therapy between the 2 largest groups: physicians (MD/DO) and dietitians. In general, and across all measured topics, physicians reported higher awareness of or familiarity with gene therapy technologies (Table II). This difference was larger for survey inquiries on safety, mechanisms, and durability, with 60% to 86% of physicians reporting awareness of these specific topics compared with 9% to 22% of dietitian respondents. Although the survey respondents reported concerns about the safety of AAV-based gene therapy, 75% (n = 47 of 63) reported having a low or moderate level of knowledge regarding immunogenicity.
Table IIDifferences between physicians and dietitians in awareness of and communication about gene therapy technologies under investigation.
General Knowledge of Gene Therapy Research
Physicians (n = 35)
Dietitians (n = 23)
Awareness/familiarity with gene therapy with viral vector technologies
Awareness/familiarity with specific topics related to gene therapy with viral vector technologies
Affinity for certain target tissues/cells
Transduction efficiency of the viral vector
Cellular turnover and durability of effect
Due to the small number of nurses, nurse practitioners, and genetic counselors, they were not included in this analysis.
Most respondents expressed low confidence in their abilities to discuss, educate, or counsel patients with IMDs and/or their caregivers across a range of topics (Figure 2). Across all topics, physicians reported more confidence than dietitians in discussing gene therapy research with patients with IMDs and/or their caregivers. Similarly, when discussing confidence in answering the questions of HCP colleagues, a higher proportion of dietitian respondents selected “not confident” or “somewhat confident” compared with physician respondents (Figure 3).
Another subset analysis was performed among respondents who pursued gene therapy–related research (n = 22 [21 of whom answered the follow-up questions]). In their conversations with patients and caregivers (Figure 2) or HCPs (Figure 3), the majority of gene therapy researchers reported feeling “confident” or “very confident” when discussing topics such as the potential removal of dietary restrictions (81% and 76%, respectively), follow-up needs (71% and 67%, respectively), the gene therapy mechanism of action (67% for both), potential safety concerns (67% and 62%, respectively), and the science of AAV-mediated gene therapy (57% for both).
Educational Needs Related to Gene Therapy Research
Nearly all respondents (94% [n = 60 of 64]) said they were interested in learning more about advancements or new developments in gene therapy research for IMDs. Of the 4 respondents who expressed a lack of interest (3 physicians, 1 dietitian), 3 reported they would wait until the modality is closer to implementation in patients with IMDs. Published literature and scientific congress abstracts and presentations were the most preferred sources for data on gene therapy research in IMDs for 95% (n = 61 of 64) and 75% (n = 48 of 64) of respondents, respectively. Other sources of information considered by respondents included rare disease organization Websites or other online resources (59% [n = 38 of 64]), industry-sponsored online resources (47% [n = 30 of 64]), industry-sponsored speaker programs (45% [n = 29 of 64]), and communications from manufacturers engaging in gene therapy research (36% [n = 23 of 64]).
Most respondents identified safety considerations (84% [n = 54 of 64]), clinical trial results (81% [n = 52 of 64]), and differences in gene therapy technologies under investigation (80% [n = 51 of 64]) as educational needs. Each topic included in the survey was considered an educational need by more than one half of respondents, except for the navigation of insurance approval/authorization procedures (48% [n = 31 of 64]) and the preparation of treatment sites for gene therapy technologies (42% [n = 27 of 64]). The most frequently selected topics for additional education were safety and efficacy (67% [n = 41 of 61]), durability of treatment effect (59% [n = 36 of 61]), and mechanism of action (54% [n = 33 of 61]). Other topics included the management of potential side effects (39% [n = 24 of 61]), potential normalization of diet or lifelong dietary changes for relevant IMDs (38% [n = 23 of 61]), patient monitoring for patients enrolled in gene therapy clinical trials (30% [n = 18 of 61]), patient education or counseling points (16% [n = 10 of 61]), and patient identification or selection (10% [n = 6 of 61]). Among dietitians, the most selected topics for more education were mechanism of action (70% [n = 16 of 23]), potential normalization of diet (70% [n = 16 of 23]), and safety and efficacy data (48% [n = 11 of 23]).
This survey broadly characterized the HCP community engaged in the management of patients with IMDs in terms of their perspectives, knowledge, and confidence gaps related to ongoing clinical research into gene therapy for IMDs. The survey respondent population was an experienced cohort of HCPs, with an average of 17 years’ experience in caring for adult and pediatric patients with IMDs. A little more than one half of participants were physicians, with more than one third dietitians. We felt that dietitians were an important clinician group to assess because they are often on the front lines of treating inherited metabolic diseases, and they are often the primary contact for patients.
A substantial majority of respondents believed there is the potential for gene therapy for some IMDs to be made available within the next 5 years; this finding was perhaps expected, given the large proportion of respondents who reported participating in ongoing gene therapy research in patients with IMDs. Most respondents reported some familiarity with the safety concerns associated with gene therapy, but the majority indicated they were unsure of the logistics and protocols involved in the delivery of gene therapy and of what impact it will have on patient management, surveillance, and follow-up.
With 180 gene therapy studies in metabolic conditions listed in ClinicalTrials.gov as either active, recruiting, enrolling by invitation, or not yet recruiting in July 2022, there is an urgent need for education on topics related to gene therapy modalities.
The majority of respondents in our study indicated they have low or moderate familiarity with key safety concerns associated with gene therapy, including AAV immunogenicity and viral shedding. In general, the rates of respondents’ familiarity were inversely correlated with the technicality of the topic, such that the highest rates of awareness were reported for safety concerns and lower rates of awareness were reported for mechanisms of gene therapy. In general, there was a trend toward agreement among respondents on the most important indicators of gene therapy success, but the relatively low percentage for each response likely reflects that the field has not yet coalesced on the most important outcomes for measuring treatment efficacy.
Importantly, only 37% of respondents reported being confident or very confident in discussing eligibility for gene therapy clinical trial enrollment with patients and/or caregivers, which could slow the pace of clinical research. However, as expected, in the subset of respondents who pursued gene therapy–related research, most were confident/very confident in having conversations with both patients/caregivers and HCP colleagues on the different aspects and potential of gene therapy.
Although gaps in knowledge were identified in all groups of HCPs, there were interesting and consistent differences in knowledge and conversational confidence between physicians and dietitians. This finding suggests a need for tailoring educational resources to suit the needs of each individual HCP group. In general, dietitians were less confident in discussing or educating patients or their caregivers on gene therapy research in IMDs compared with physicians. Across multiple domains in the survey, dietitians reported education gaps that may have reduced their confidence in communication with or future care of patients who may receive gene therapy for IMDs. The physician subpopulation, on the other hand, reported having received significant training in genetics and genomics, providing foundational knowledge to better follow the gene therapy research. Nearly all respondents would like more information about gene therapy for IMDs, and they selected published literature and scientific congresses as the most trusted educational sources to address these knowledge gaps.
Each member of the care team has different but overlapping educational needs.
Nurses and advanced practice providers (ie, nurse practitioners) may be tasked with education of the patients and their caregivers, whereas dietitians focus on providing guidance on dietary management.
Therefore, given the potential impact of gene therapy on patient care and follow-up, it is important that all HCPs who treat patients with IMDs have adequate knowledge of gene therapy. Any educational offerings should be tailored to the individual audience group (eg, primary care, dietitians, geneticists); nevertheless, there is some consistency in the modalities that can be used. For each individual gene therapy, peer-reviewed publications are the gold standard for dissemination of the results of clinical trials. However, when discussing the benefits, risks, rationale, and appropriate populations for gene therapy as a whole, continuing medical education programs may be of benefit as they have been shown to positively affect health care provider behavior, with subsequent improvements in patient health outcomes.
Effectiveness of continuing medical education: updated synthesis of systematic reviews.
Accreditation Council for Continuing Medical Education.2014; : 1-19
Targeted review articles are another option as they can address specific knowledge gaps. Case studies, which can be a component of almost all forms of education (including review articles), may be particularly applicable as education tools in the gene therapy and IMD fields because they provide practical information to enhance clinical knowledge and improve clinical skills, allow customization, induce learning on a deeper level, and are particularly relevant when patient education is an important component of care.
HCPs who exhibit low levels of familiarity with emerging treatments could weaken the patient's or caregiver's confidence in the care team, impeding overall disease management. One survey of parents and caregivers of children with rare diseases reported that low levels of knowledge or support from HCPs can lead to treatment dissatisfaction and stress.
As a complement to the resources provided to them in their child's clinic, most parents sought information from Internet-based sources about their child's diagnosis, symptoms, and care, using their judgment to evaluate the relevancy and accuracy of the information.
Outreach efforts to educate patients and caregivers, on the other hand, can improve patient care. Letters from PKU clinics communicating information on treatment guidelines and new treatments to their patients who had been lost to follow-up led to some patients re-engaging with their health care providers.
Thus, improving HCP familiarity with gene therapy can provide the foundation for better relationships between HCPs, patients, and caregivers for improved health outcomes.
There were challenges associated with conducting this survey, especially during the COVID-19 pandemic. This survey was originally designed to be conducted during a major IMD-related scientific congress in 2020, but the event was cancelled because of health risks and international travel restrictions. As an alternative, we conducted the study solely through an Internet-based survey platform, which may have limited participation, particularly to those regions with good Internet access such as the United States, which accounted for 83% of respondents. However, the electronic platform may have also led to increased participation among those who would not normally attend such conferences due to the need to travel; both the 2020 Society for Inherited Metabolic Disorders and Genetic Metabolic Dietitians International conferences were to be held in Texas in the United States. A total of 19% of participants were from outside the United States, but without knowing the numbers of foreign participants that normally attend these meetings in person, it is not known if this is a higher or lower percentage than what would have been achieved if the survey was conducted at a meeting. The respondents provided their insights on aspects of conducting gene therapy clinical trials under the shadow of the pandemic, including travel concerns, concerns about room-occupancy safety standards, potential for incomplete compliance, and the expenses of conducting clinical research, which may have influenced their responses. Also, these questions were designed to provide a broad overview of participants’ thoughts on this topic at the time, and they should be viewed in that context.
Conclusions from this survey are constrained by the limited population of HCPs who received the Web link to this survey and the small number of responses. A larger sample size and/or different targeting would have permitted a better understanding of the educational needs of nurses and nurse practitioners. Moreover, HCPs needed to be actively monitoring their e-mail accounts to learn about the survey. The survey was offered only in English, reducing the opportunity for non-English speakers to participate. All respondents were from the United States, Europe, or Canada. Looking at the worldwide distribution of active and recruiting clinical trials of gene therapy for metabolic diseases, the majority (72%) are based in North America, with 39% based in the European Union. Thus, geographically, our survey population is probably generalizable to the population of HCPs in the field. In addition, we did not perform testing of the survey for reliability or validity, nor did we have an objective source to confirm the clinical experience of these respondents.
This study highlights the fact that clinical research into gene therapy and, potentially, the incorporation of gene therapy into real-world practice, will require all members of the multidisciplinary team to be prepared to discuss this modality and its potential place in therapeutic management. Despite the limitations intrinsic in survey research and the small number of respondents, these results show that there is a significant knowledge gap in this area and provide an initial framework for HCP outreach. Addressing educational needs about gene therapy will improve HCP confidence when having these important conversations with patients and caregivers. We anticipate that this confidence will, in turn, increase the trust and confidence patients have in their HCPs and significantly improve their experience of managing their rare IMD.
BioMarin Pharmaceutical, Inc, funded the development, conduct, and analysis of this survey. Malik Cobb, PA-C (The Lockwood Group) contributed to the study design, and medical writing assistance was provided by Katherine Stevens-Favorite, PhD, and Meredith Rogers, MS, CMPP, of The Lockwood Group, and was supported by BioMarin Pharmaceutical, Inc.
All authors contributed equally to the conceptualization, design, data analysis, data interpretation, and writing and review of the manuscript.
Declaration of Interest
J. Hansen: Consulting fees from Aeglea, BioMarin Pharmaceutical (prior to becoming an employee), and Nutricia; and received payment or honoraria for speaking from Met Ed, Nutricia, and Vitaflo. J. Hansen began employment with BioMarin Pharmaceutical in August 2021 and holds stock/stock options in BioMarin Pharmaceutical. R. Ramachandran: Consulting fees from BioMarin Pharmaceutical. J. Vockley: Supported by the National Institutes of Health (grant 5R01NR01699); and has conducted contracted research for BioMarin Pharmaceutical, Homology Pharmaceuticals, and PTH Pharmaceuticals.
The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.
Data presented in this paper are available upon request.