Lung Inflammatory Genes in Cystic Fibrosis and Their Relevance to Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapies

Round 1

Reviewer 1 Report

Review (Genes, mdpi): Lung Inflammatory Genes in Cystic Fibrosis and Their Relevance to CFTR Modulator Therapies. A. Carbone et al.

General comments

This manuscript is a review of the roles played by lung inflammatory genes in CF, and the effect of CFTR modulators. It is comprehensive, well referenced and generally well written. As the review covers the intended ground, and is clear and informative, I have no comments to make beyond the following general observations:

1. It is necessary to check and modify the English language throughout the manuscript, and this is the case from the abstract onwards. I suggest revision by a native English speaker or another colleague with fluency in English language.

2. There are many minor typographical errors throughout the manuscript. It is important that these are corrected, and I suggest the authors read through the text word for word in order to identify and correct any such mistakes. As I cannot proof-read the entire document, I give here some examples from the first few pages, but there are many others that require attention.

Line 40: “F08del” should be F508del

Line 40: “plasma membrane” should be two words

Line 88: misspelling - the word should be “phagocytosed”

Line 106: misspelling - “recognise”

Line 107: “subject-specific” is mistyped

Review (Genes, mdpi): Lung Inflammatory Genes in Cystic Fibrosis and Their Relevance to CFTR Modulator Therapies. A. Carbone et al.

General comments

This manuscript is a review of the roles played by lung inflammatory genes in CF, and the effect of CFTR modulators. It is comprehensive, well referenced and generally well written. As the review covers the intended ground, and is clear and informative, I have no comments to make beyond the following general observations:

1. It is necessary to check and modify the English language throughout the manuscript, and this is the case from the abstract onwards. I suggest revision by a native English speaker or another colleague with fluency in English language.

2. There are many minor typographical errors throughout the manuscript. It is important that these are corrected, and I suggest the authors read through the text word for word in order to identify and correct any such mistakes. As I cannot proof-read the entire document, I give here some examples from the first few pages, but there are many others that require attention.

Line 40: “F08del” should be F508del

Line 40: “plasma membrane” should be two words

Line 88: misspelling - the word should be “phagocytosed”

Line 106: misspelling - “recognise”

Line 107: “subject-specific” is mistyped

Author Response

This manuscript is a review of the roles played by lung inflammatory genes in CF, and the effect of CFTR modulators. It is comprehensive, well referenced and generally well written. As the review covers the intended ground, and is clear and informative, I have no comments to make beyond the following general observations:

Q1. It is necessary to check and modify the English language throughout the manuscript, and this is the case from the abstract onwards. I suggest revision by a native English speaker or another colleague with fluency in English language.

A1. We thank the Reviewer for her/his positive appraisal of our work. We have checked the English language throughout the whole manuscript, hoping that is now satisfying.

Q2. There are many minor typographical errors throughout the manuscript. It is important that these are corrected, and I suggest the authors read through the text word for word in order to identify and correct any such mistakes. As I cannot proof-read the entire document, I give here some examples from the first few pages, but there are many others that require attention.

Line 40: “F08del” should be F508del

Line 40: “plasma membrane” should be two words

Line 88: misspelling - the word should be “phagocytosed”

Line 106: misspelling - “recognise”

Line 107: “subject-specific” is mistyped

A2. We have corrected all the minor typographical errors, not only those indicated by the Reviewer.

Reviewer 2 Report

The authors have presented an updated comprehensive review of potential genetic variants or polymorphisms that could contribute to modifications of respiratory disease severities in CF patients with a focus on inflammatory-immune categories including genetic processes contributing to a disarray of NF-kB and inflammasome pathways.  

These interacting pathways are believed to represent an important category of "modifier genes" contributing to the variations in clinical  phenotypes of similar CFTR genotypes.  Strengths of the review include the emphasis on variants of inflammatory-immune genes influencing CF lung disease severity with focus on those described in the last 15 years during the era of the paradigm shift emerging from the use of CFTR modulator therapies and the particular emphasis on modulator therapy effects on specific cell trpes with strong relationships to inflammatory-immune processes.  The review makes a strong and timely contribution to the CF and inflammatory-immune system communities.  This reviewer only has very minor comments to make for authors to consider in minimal revision.

COMMENTS

1.  Line 65, elastin is not a serine protease.  You probably mean leukocyte elastase.

2.  Line 353-354, "among which CF" seems awkward.

3. Another limitation that could be mentioned toward the end is that no attempt was made to identify dr nova effects of the modifier molecules themselves and which could be influencing off target non-influencing CFTR effects and  be contributing to the increasing spectrum of rare side effects/toxicities   being reported  in a few patients

Author Response

The authors have presented an updated comprehensive review of potential genetic variants or polymorphisms that could contribute to modifications of respiratory disease severities in CF patients with a focus on inflammatory-immune categories including genetic processes contributing to a disarray of NF-kB and inflammasome pathways.  

These interacting pathways are believed to represent an important category of "modifier genes" contributing to the variations in clinical  phenotypes of similar CFTR genotypes.  Strengths of the review include the emphasis on variants of inflammatory-immune genes influencing CF lung disease severity with focus on those described in the last 15 years during the era of the paradigm shift emerging from the use of CFTR modulator therapies and the particular emphasis on modulator therapy effects on specific cell trpes with strong relationships to inflammatory-immune processes.  The review makes a strong and timely contribution to the CF and inflammatory-immune system communities.  This reviewer only has very minor comments to make for authors to consider in minimal revision.

 We thank the Reviewer for her/his positive appraisal of our work.

COMMENTS

1.  Line 65, elastin is not a serine protease.  You probably mean leukocyte elastase.

Thanks, corrected.

2.  Line 353-354, "among which CF" seems awkward.

Thanks, changed.

3. Another limitation that could be mentioned toward the end is that no attempt was made to identify dr nova effects of the modifier molecules themselves and which could be influencing off target non-influencing CFTR effects and  be contributing to the increasing spectrum of rare side effects/toxicities   being reported  in a few patients

We thank the Reviewer for this comment. We have added to the revised version a novel paragraph concerning these issues in the Discussion along with new references (lines 557-561).