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PONE-D-24-09705Gene Therapy for Alzheimer’s Disease: Clinicians’ perspectives on patient needsPLOS ONE

Dear Dr. Boucher,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. After careful consideration by 2 Reviewers and an Academic Editor, all of the critiques of both Reviewers must be addressed in detail in a revision to determine publication status. If you are prepared to undertake the work required, I would be pleased to reconsider my decision, but revision of the original submission without directly addressing the critiques of the Reviewers does not guarantee acceptance for publication in PLOS ONE. If the authors do not feel that the queries can be addressed, please consider submitting to another publication medium. A revised submission will be sent out for re-review. The authors are urged to have the manuscript given a hard copyedit for syntax and grammar.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: N/A

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Much of your work may be applicable to the use of monoclonal antibodies. Would you consider doing a similar study for that indication?

More importantly, your work on gene therapy for AD is more applicable in the near term to APP, PS1 and PS2 mutations. This could be mentioned in your discussion. Consider working with clinicians participating in the DIAN cohort studies and persons at risk of carrying such genes. You may get different answers than from your current study.

Reviewer #2: Overall

The researchers aimed to understand clinicians’ perspectives regarding gene therapy, their understanding of patients’ views, and potential barriers and facilitators to its use as a future treatment for Alzheimer’s disease (AD).

Given advances in developing these therapies and the lack of knowledge about clinicians’ and patients’ perspective, this is a topical study. It’s important to include the perspectives of the people who might be affected by new innovative treatments at an early stage.

The researchers identified gaps in knowledge, a need for educational materials, and barriers such as cost, difficulty to understand such complex interventions and lack of trust in health care systems.

However, my main concerns are:

- It remains unspecified what is meant by “gene therapies”, for whom this are intended, in what stage, etcetera. Although I understand that this may vary somewhat, by leaving it so vague, the findings could be applicable to any new medical intervention for Alzheimer’s disease.

- The sample population is small (10 health care providers) and not very representative (4 have a Master’s Degree as highest education). Based on this I doubt to what extent these findings may reflect and be generalizable to the perspectives of the clinicians who would discuss gene therapies with patients if and when they are introduced.

- In addition, potential patients are referred to as individuals who are cognitively impaired, and potentially unable to perform activities of daily living, to the extent they are no longer competent to make their own decisions. To the best of my knowledge, these therapies are generally intended for patients in earlier stages of the disease, where these challenges play a smaller role and other barriers apply (for example, related to treating relatively healthy individuals with invasive and risky therapies).

- In relation to this, the interview guide does not seem to be based on literature or findings, and only incorporates feedback from three clinicians with expertise in social work and neurology. The questions focus on specific topics, such as understanding, costs and tensions in health care delivery which correspond directly to the findings. So, I don’t feel like this is an exploration of which concerns, barriers and facilitators might be involved, but a specification of certain pre-specified aspects.

- Lastly, as this qualitative study is not reported in accordance to the Consolidated criteria for reporting qualitative research (COREQ) checklist or Standards for reporting qualitative research (SRQR) checklist (the authors don’t report adhering to guidelines), I doubt whether it is reproducible and generalizable.

Thus, while the topic is very relevant and I commend the authors for investigating it, I believe the study can be improved in several aspects. So rather than spending my time commenting on what is already good, I tried to address what could be done better. So I hope my comments may helpful for the authors to accomplish this.

In general

- Please add line numbers to facilitate reviewing.

Abstract

- Title: “Gene Therapy for Alzheimer’s Disease: Clinicians’ perspectives on patient needs” seems to suggest this is about patients need, while only clinicians were interviews. As this does not correspond directly to the findings and is not the best way to study patients’ needs, I suggest changing it.

- Introduction: The aim does not correspond to the aim as specified in the introduction (facilitators are missing)

- Methods: “Personal morals” were not addressed in this study (these generally refer to an individual's principles or standards of behavior) and are therefore not synonymous to religious or spiritual aspects.

- Results: These findings don’t seem to entirely correspond to the headings and findings in the manuscript. And while I can see how patients may find it difficult to understand gene therapy, I would strongly suggest refraining from claiming that they lack the education or ability to do so. These therapies are not introduced in clinical practice yet, the fact that ten clinicians expect that they are unable to comprehend this, does not make it a scientifically supported finding and in my humble opinion this could be perceived as derogatory and offensive, which I am sure was not intended by the authors.

- Discussion/conclusion: I would say clinicians need to be educated themselves and learn to explain this to their patients, rather than merely being aware of their patients’ needs and their own gaps in knowledge.

Introduction

- “that poses social and economic challenges for clinicians, health systems, patients, and families worldwide”: I’d say these are first and foremost challenges for patients, their families, society and the health care system, rather than clinicians.

- The NIA-AA diagnostic framework is intended for research, not clinical practice. and it does not define Alzheimer’s Disease as A+T+N+ but as A+T+. Also, it is not clear to me how biological disease criteria relate to gene therapies.

- How do treatments for sickle cell disease fit in a listing of treatments for AD?

- “E (APOE) gene impart increased genetic risk for AD”: not necessarily, it could also decrease.

- “Every individual carries one of three possible alleles”: they carry two.

- “As rates of AD and AD-related deaths increase in the population, there is high demand from patients, caregivers and patient advocates for effective disease-modifying therapies”: I’d say they ask this because it is a devastating disease and the prevalence is already very high and rising (although according to some reports not as fast as projected), rather the mere fact that deaths are rising.

- “Disparities in dementia care are well documented.” While important, this is a rather abrupt introduction of an entirely new topic.

- “The importance of how clinicians approach complex treatments and clinical decision- making with AD patients and their families cannot be understated.” I suggestion adding a few sentences here and there to smooth these transitions.

- “research exploring how patients and caregivers understand gene therapy as an emerging treatment for AD is lacking.[13] We took a high-level approach, seeking to understand how clinician’s themselves perceive gene therapy and their understanding of patients’ awareness of gene therapy”: asking clinicians is not the best way to study patients perspectives. If you want to study patients’ perspective I would suggest including them in the study population. Or if you only interview clinicians, report clinicians’ perspectives. Again, as far as I know, these gene therapies are not introduced in clinical practice yet, so asking one group what another group may or may not understand about unspecified and unapproved treatments is in my opinion quite an unnecessary stretch.

- I strongly suggest specifying here what is meant by these novel gene therapies, for which patients they are intended, in which stage, with what target, as well as potential benefits and harms, and what exactly may be so difficult to explain and understand. As ApoE is discusses somewhat out of the blue, I gather the authors may have therapies targeting this gene in mind, whereas CRISPR-Cas interventions to alter causal mutations of dominantly inherited Alzheimer’s Disease may introduce a different applications, which do not necessarily include the same views, barriers and facilitators. As this is the topic of this study, it should be specified, at least to some extent. In addition, I would be interested in literature on views, barriers, and facilitators related to gene therapies for other diseases that have already been approved and introduced in clinical practice, as they give insights and a starting point for gene therapies in AD.

Methods:

- “We conducted semi-structured interviews with providers who would play a pivotal role in guiding patients through decisions regarding gene therapy for Alzheimer’s disease.” Please specify this.

- “we collaborated with key health system leaders who suggested clinicians appropriate for the study across disciplines”: again, this is quite vague.

- “The multidisciplinary research team created a semi-structured interview guide complete with open-ended interview questions and probes.”: How? Based on what literature, of which findings? Why include these topics and not others?

- “Three clinicians with social work and neurology expertise in our health system reviewed the guide, and we incorporated their feedback.” What makes them qualified to do so?

- “domains queried in the interview guide included: cost, access, and quality[15]––predominant tensions driving healthcare delivery––as well as patient and clinician concerns around establishing understanding of gene therapy as a treatment. Additionally, we asked about personal morals, including religion and spirituality.”: Why focus on this selection of topics?

- How long were the interviews?

- It would be insightful to include the topic guide and script for the semi-structured interviews.

- How were participants informed about the topic of interest (gene therapies), how was this defined?

Analysis

- “When further observations and analysis were no longer generating new or discrete themes, the study team stopped interviews and recruitment” I find it somewhat unexpected that data saturation was reached after only ten interviews, when they concern such a complex topic.

Results:

- “10 in-depth interviews with clinicians” Please specify what is meant by clinicians. General practitioners or neurologists? In primary care or memory clinics? Academic centers? Did they have experience with gene therapies in clinical trials in this population?

- Sample characteristics: based on this, I don’t think this sample is representative of the physicians who would actually discuss gene therapies with potential patients, given their education and clinical discipline.

- “Analysis resulted in a focus on three main themes with related subthemes – 1) Understanding of gene therapy and Alzheimer’s disease 2) Consideration of inequity (care access, disease awareness along with education level, family support, trust in care systems); and 3) Considerations in decision-making (religious/spiritual beliefs and method of treatment delivery as a decision-making tools).”: How do these correspond to the results reported in the abstract?

Gaps in understanding of gene therapy and Alzheimer’s disease

- “Our clinician interviewees noted that, to provide optimal care to people living with Alzheimer’s disease (AD), healthcare providers should consider the patients’ own preferences.”: Yet everything listed in this paragraph seems to concerned with patients characteristics, rather than the patients’ own preferences?

- Also, how does this relate to understanding of AD and gene therapy?

Consideration of inequity

- “gene therapy––the details of which may even stump a knowledgeable clinician.”: I suggest reconsidering or rephrasing this.

Results in general

These results are very general and rather superficial and seems to apply any new medical therapy for AD, rather than gene therapy specifically.

The findings seem to focus mostly on barriers, where are the facilitators reported…?

In addition, potential patients are referred to as individuals who are cognitively impaired, and potentially unable to perform activities of daily living, to the extent they are no longer competent to make their own decisions. To the best of my knowledge, these therapies are generally intended for patients in earlier stages of the disease, where these challenges play a smaller role and other barriers apply (for example, related to treating relatively healthy individuals with invasive and risky therapies).

Discussion

- “We explored patient needs regarding the future of AD gene therapy from the clinician’s perspective.” Again, I think this study should focus on clinicians’ perspectives alone. Or include patients in the sample population.

- “While colleagues work diligently on the biological science of gene therapy, our team posited that many barriers potentially exist to the successful rollout of gene therapy in the practical world of patient care.”: Our team…?

Conclusion

- “Clinicians working in this area see the challenges ahead and readily suggest what might be done to mitigate them.”: Were these suggestions included in the results?

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-09705R1Clinician’s Perspectives on Gene Therapy for Alzheimer’s Disease: A Qualitative StudyPLOS ONE

Dear Dr. Boucher,

Thank you for resubmitting your work to PLOS ONE. Please make the corrections posed by Reviewer #2 so I can render a decision on this manuscript.

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. 

Reviewer #1: Yes

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously? 

Reviewer #1: N/A

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you answering my questions. Hopefully you will follow-up on this topic in the future. Consider reaching out to the DIAN network.

Reviewer #2: Dear authors,

Although most of my comments have been addressed appropriately, I still have one major issue:

The introduction has been rewritten and expanded to clarify that this paper addresses clinician's views on gene therapies targeted at the APOE4 allele.

However the methods section now states that participants were provided the following - very general - definition of gene therapies: "Gene therapy is an experimental technique that uses genes - a unit of heredity written in our DNA - to treat or prevent disease. In the future, this technique may allow health care providers to treat a disorder, such as Alzheimer’s disease by adding or changing a gene in a patient's cells."

Yet ApoE4 is not mentioned anywhere in the interview guide. Moreover, most questions, except for the first one, relate to "new Alzheimer’s care and treatment strategies", or "a treatment is able to stop Alzheimer’s" or "an Alzheimer’s treatment". Some do not even mention treatment of any kind ("6. According to the Alzheimer’s Association, Black Americans are diagnosed with Alzheimer’s at a later stage than White Americans. a. Why do you think this happens?"). The interview guide does not seem to focus on gene therapies targeted at ApoE4, or even gene therapies in general, but at any kind of hypothetical new strategy for treatment or care.

I think this is problematic, as the clinicians who were interviewed, seemed to talk about treatments in a very broad sense, given their comments about patients' decision-making capacities, assuming they are cognitively impaired, even confined to bed, or have “progressed to such a degree that it seems that any further treatment would just be burdensome”. In my opinion it is extremely unlikely that gene therapies would be offered to patients with MCI or dementia. So I get the impression that the results do not relate to gene therapies targeted at ApoE4, but to any kind of treatment or care in any stage of the disease.

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Reviewer #1: No

Reviewer #2: No

**********While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

==============================

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

Stephen D. Ginsberg, Ph.D.

Section Editor

PLOS ONE

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Clinician’s Perspectives on Gene Therapy for Alzheimer’s Disease: A Qualitative Study

PONE-D-24-09705R2

Dear Dr. Boucher,

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