Reviewer ’s report  
 
Title: Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice  
 
Version: 1 Date: 12 Feb 2018  
 
Reviewer: Jordi Barquinero  
 
Reviewer's report:  
 
The work performed by Yadak et al. analyzes some aspects of the  intestinal pathology in three 
MNGIE patients, one untreated and two after receiving an allogeneic HSCT, as well in an animal 
model of the disease, Tymp -/- Upp1 -/- double KO mice. The experimental work is well designed 
and well performed and the results ob tained are relevant and confirm previous reports on the 
small intestine muscle pathology and the loss of Cajal cells in these patients. The major 
drawback, in my opinion, is their main conclusion suggesting that HSCT may be insufficient to 
restore intestin al neuropathology, which is hard to substantiate based only on the data presented 
due to the relatively short follow up in the two patients receiving HSCT (18 days and 6 months), 
plus the potential effects of an allogeneic HSCT on the small intestine, limi tations that are 
recognized by the authors.  
 
Minor comments:  
p4. Please specify whether the two control groups are KO mice receiving untreated BM cells 
from donor KO and WT mice.  
p14 (Fig 1 legend). SM: tunica submucosa  
p15 (Fig 2 legend). "H&E stain of th e small intestine shows recovery of normal thickness...". It 
is more likely than in the treated mice the thickness loss is prevented rather than recovered, as it 
is not apparent at the age of two months, when the animals receive the gene therapy. The same in 
the discussion, "The observed atrophy of the tunica muscularis propria was recovered...".  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
  
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comme nts to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessme nt in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests,  considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the futur e? 
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the conten t of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competin g interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice  
 
Version: 1 Date: 12 Feb 2018  
 
Reviewer: Jordi Barquinero  
 
Reviewer's report:  
 
The work performed by Yadak et al. analyzes some aspects of the  intestinal pathology in three 
MNGIE patients, one untreated and two after receiving an allogeneic HSCT, as well in an animal 
model of the disease, Tymp -/- Upp1 -/- double KO mice. The experimental work is well designed 
and well performed and the results ob tained are relevant and confirm previous reports on the 
small intestine muscle pathology and the loss of Cajal cells in these patients. The major 
drawback, in my opinion, is their main conclusion suggesting that HSCT may be insufficient to 
restore intestin al neuropathology, which is hard to substantiate based only on the data presented 
due to the relatively short follow up in the two patients receiving HSCT (18 days and 6 months), 
plus the potential effects of an allogeneic HSCT on the small intestine, limi tations that are 
recognized by the authors.  
 
Minor comments:  
p4. Please specify whether the two control groups are KO mice receiving untreated BM cells 
from donor KO and WT mice.  
p14 (Fig 1 legend). SM: tunica submucosa  
p15 (Fig 2 legend). "H&E stain of th e small intestine shows recovery of normal thickness...". It 
is more likely than in the treated mice the thickness loss is prevented rather than recovered, as it 
is not apparent at the age of two months, when the animals receive the gene therapy. The same in 
the discussion, "The observed atrophy of the tunica muscularis propria was recovered...".  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
  
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comme nts to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessme nt in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests,  considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the futur e? 
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the conten t of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competin g interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Transplantation, gene therapy and intestinal pathology in MNGIE patients and mice  
 
Version: 1 Date: 12 Feb 2018  
 
Reviewer: Jordi Barquinero  
 
Reviewer's report:  
 
The work performed by Yadak et al. analyzes some aspects of the  intestinal pathology in three 
MNGIE patients, one untreated and two after receiving an allogeneic HSCT, as well in an animal 
model of the disease, Tymp -/- Upp1 -/- double KO mice. The experimental work is well designed 
and well performed and the results ob tained are relevant and confirm previous reports on the 
small intestine muscle pathology and the loss of Cajal cells in these patients. The major 
drawback, in my opinion, is their main conclusion suggesting that HSCT may be insufficient to 
restore intestin al neuropathology, which is hard to substantiate based only on the data presented 
due to the relatively short follow up in the two patients receiving HSCT (18 days and 6 months), 
plus the potential effects of an allogeneic HSCT on the small intestine, limi tations that are 
recognized by the authors.  
 
Minor comments:  
p4. Please specify whether the two control groups are KO mice receiving untreated BM cells 
from donor KO and WT mice.  
p14 (Fig 1 legend). SM: tunica submucosa  
p15 (Fig 2 legend). "H&E stain of th e small intestine shows recovery of normal thickness...". It 
is more likely than in the treated mice the thickness loss is prevented rather than recovered, as it 
is not apparent at the age of two months, when the animals receive the gene therapy. The same in 
the discussion, "The observed atrophy of the tunica muscularis propria was recovered...".  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
  
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comme nts to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessme nt in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests,  considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the futur e? 
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the conten t of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competin g interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant