Opportunities and challenges for the use of induced pluripotent stem cells in modelling neurodegenerative disease

Adult-onset neurodegenerative diseases are among the most difficult human health conditions to model for drug development. Most genetic or toxin-induced cell and animal models cannot faithfully recapitulate pathology in disease-relevant cells, making it excessively challenging to explore the potential mechanisms underlying sporadic disease. Patient-derived induced pluripotent stem cells (iPSCs) can be differentiated into disease-relevant neurons, providing an unparalleled platform for in vitro modelling and development of therapeutic strategies. Here, we review recent progress in generating Alzheimer's, Parkinson's and Huntington's disease models from patient-derived iPSCs. We also describe novel discoveries of pathological mechanisms and drug evaluations that have used these patient iPSC-derived neuronal models. Additionally, current human iPSC technology allows researchers to model diseases with 3D brain organoids, which are more representative of tissue architecture than traditional neuronal cultures. We discuss remaining challenges and emerging opportunities for the use of three-dimensional brain organoids in modelling brain development and neurodegeneration.


Is the length of the paper justified? Yes
Should the paper be seen by a specialist statistical reviewer? No Is it clear how to make all supporting data available? Not Applicable

Do you have any ethical concerns with this paper? No
Comments to the Author This is a timely, interesting and rather comprehensive review on the use of human iPSCs in modeling neurodegenerative diseases. 3 main neurodegenerative diseases were discussed, i.e. AD, PD and HD. Overall, the write up is informative and the tables provided that summarize the various iPSC-linked disease models generated thus far by different groups serve as a good resource.
Notwithstanding the above, I have some comments/suggestions that might help to improve the article further, as discussed below: 1. Although current animal models of neurodegenerative diseases are well recognized for their limitations, they have nonetheless shed important insights into the pathogenesis of various neurodegenerative disorders. Importantly, they provide the associated behavioral phenotype (e.g. cognitive or motor impairments) that could be quantified, which also serve as useful readouts for drug evaluation. This is something that 2D and even 3D iPSC-based disease models cannot recapitulate. The authors may wish to take this into consideration in their discussion.
2. The maturity of iPSC-derived neurons and the time for them to age sufficiently to manifest the disease-associated phenotypes is indeed an issue (p. 4). The authors stated that the issue is addressed by "the use of multiple well-characterized iPSC lines and isogenic controls". Arguably, these lines may resolve the variability issue but not the time issue.
3. Related to the above, for age-related neurodegenerative diseases like AD and PD, substantial length of time is needed for the phenotype to manifest. Hence, the use of progerin-induced aging as a strategy to accelerate the aging process, which the authors have also highlighted. However, is progerin-induced aging an appropriate model for AD and PD? This is something that merits discussion.
4. The section "Modeling neurodegenerative diseases with by 3D brain model" is grammatically incorrect (i.e. with or by?). Importantly, the reported generation and characterization of 3D ventral midbrain organoid model that is relevant to PD (e.g. Jo et al., 2017 Cell Stem Cell) was not discussed.
5. The authors have discussed several limitations surrounding current 3D organoid models. One major limitation with the ventral midbrain model is its primitive structure, which in no way recapitulate the nigrostriatal pathway that degenerates in human PD brain. The authors might want to include this point in their revised discussion.

05-Nov-2018
Dear Dr Wu We are pleased to inform you that your manuscript RSOB-18-0177 entitled "Opportunities and challenges for the use of induced pluripotent stem cells in modeling neurodegenerative disease" has been accepted by the Editor for publication in Open Biology. The reviewer has recommended publication, but also suggest some minor revisions to your manuscript. Therefore, we invite you to respond to the reviewer's comments and revise your manuscript.
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Online supplementary material will also carry the title and description provided during submission, so please ensure these are accurate and informative. Note that the Royal Society will not edit or typeset supplementary material and it will be hosted as provided. Please ensure that the supplementary material includes the paper details (authors, title, journal name, article DOI Comments to the Author(s) This is a timely, interesting and rather comprehensive review on the use of human iPSCs in modeling neurodegenerative diseases. 3 main neurodegenerative diseases were discussed, i.e. AD, PD and HD. Overall, the write up is informative and the tables provided that summarize the various iPSC-linked disease models generated thus far by different groups serve as a good resource.
Notwithstanding the above, I have some comments/suggestions that might help to improve the article further, as discussed below: 1. Although current animal models of neurodegenerative diseases are well recognized for their limitations, they have nonetheless shed important insights into the pathogenesis of various neurodegenerative disorders. Importantly, they provide the associated behavioral phenotype (e.g. cognitive or motor impairments) that could be quantified, which also serve as useful readouts for drug evaluation. This is something that 2D and even 3D iPSC-based disease models cannot recapitulate. The authors may wish to take this into consideration in their discussion.
2. The maturity of iPSC-derived neurons and the time for them to age sufficiently to manifest the disease-associated phenotypes is indeed an issue (p. 4). The authors stated that the issue is addressed by "the use of multiple well-characterized iPSC lines and isogenic controls". Arguably, these lines may resolve the variability issue but not the time issue.
3. Related to the above, for age-related neurodegenerative diseases like AD and PD, substantial length of time is needed for the phenotype to manifest. Hence, the use of progerin-induced aging as a strategy to accelerate the aging process, which the authors have also highlighted. However, is progerin-induced aging an appropriate model for AD and PD? This is something that merits discussion.
4. The section "Modeling neurodegenerative diseases with by 3D brain model" is grammatically incorrect (i.e. with or by?). Importantly, the reported generation and characterization of 3D ventral midbrain organoid model that is relevant to PD (e.g. Jo et al., 2017 Cell Stem Cell) was not discussed.
5. The authors have discussed several limitations surrounding current 3D organoid models. One major limitation with the ventral midbrain model is its primitive structure, which in no way recapitulate the nigrostriatal pathway that degenerates in human PD brain. The authors might want to include this point in their revised discussion.

03-Dec-2018
Dear Dr Wu We are pleased to inform you that your manuscript entitled "Opportunities and challenges for the use of induced pluripotent stem cells in modeling neurodegenerative disease" has been accepted by the Editor for publication in Open Biology.
You can expect to receive a proof of your article from our Production office in due course, please check your spam filter if you do not receive it within the next 10 working days. Please let us know if you are likely to be away from e-mail contact during this time.
Thank you for your fine contribution. On behalf of the Editors of Open Biology, we look forward to your continued contributions to the journal. Sincerely, The Open Biology Team mailto: openbiology@royalsociety.org MS ID#: RSOB-18-0177 Current Title: Opportunities and challenges for the use of induced pluripotent stem cells in modeling neurodegenerative disease Reviewer's Comments to Author: Referee: Comments to the Author(s) This is a timely, interesting and rather comprehensive review on the use of human iPSCs in modeling neurodegenerative diseases. 3 main neurodegenerative diseases were discussed, i.e. AD, PD and HD. Overall, the write up is informative and the tables provided that summarize the various iPSC-linked disease models generated thus far by different groups serve as a good resource.
Notwithstanding the above, I have some comments/suggestions that might help to improve the article further, as discussed below: 1. Although current animal models of neurodegenerative diseases are well recognized for their limitations, they have nonetheless shed important insights into the pathogenesis of various neurodegenerative disorders. Importantly, they provide the associated behavioral phenotype (e.g. cognitive or motor impairments) that could be quantified, which also serve as useful readouts for drug evaluation. This is something that 2D and even 3D iPSC-based disease models cannot recapitulate. The authors may wish to take this into consideration in their discussion.

Response:
We thank reviewers for this and other thoughtful suggestions; we believe that addressing each one has greatly improved the quality of our manuscript. We agree that animal models provide important insights into the pathogenesis of neurodegenerative diseases, and it is inarguable that in vitro iPSC-based models cannot recapitulate the behavioral phenotypes, such as motor dysfunction in PD and impaired cognition in AD. Thus, we have revised the Conclusion accordingly, and we now suggest the use of iPSC-based models in combination with animal models for drug development. In this way, novel interventions can be evaluated in these complementary systems prior to clinical application (Page 18, Line 579).
2. The maturity of iPSC-derived neurons and the time for them to age sufficiently to manifest the diseaseassociated phenotypes is indeed an issue (p. 4). The authors stated that the issue is addressed by "the use of multiple well-characterized iPSC lines and isogenic controls". Arguably, these lines may resolve the variability issue but not the time issue.

Response:
We revised the Introduction accordingly, mentioning that some issues of timing could be potentially addressed by multiple treatments or long-term 3D organoid cultures. For most diseases of aging, multiple treatments are required to promote the expression of disease-associated phenotypes in cellular models. This approach may also be improved by utilizing long-term 3D organoid cultures. These complex structures