A Mini-Review on Gene Therapy in Glaucoma and Future Directions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Abstract:

A good abstract of a review should briefly introduce the background of the review's topic and then focus on summarizing the main content, key findings, viewpoints, and conclusions of the reviewed literature. It should not overly describe the process and results of the literature selection. I strongly suggest the authors read and refer to some high-quality published reviews.

Introduction:

(1)     Lines 44-50: The sentence “Every cell in our body … may impact our bodies and our health.” is redundant and could be removed for conciseness. This section could be improved by adding information about the surgical treatment options for glaucoma and the associated current challenges.

(2)     The structure of the entire manuscript is not aligned with the standard format for review articles. It is highly recommended to refer to the format and structure of review articles previously published in this journal.

(3)     Line 72: Based on my understanding, Figure 1 depicts the overall history of gene therapy rather than its development specifically in glaucoma treatment. Is the word "in glaucoma" accurate?

Results:

(1)     Lines 133-139: The presentation of these results, including Figure 2, follows the format and requirements of a meta-analysis. Please carefully differentiate this and make the necessary revisions accordingly.

(2)     Lines 144-165: "The content of these two paragraphs does not align well with subheading 2.1. 'Gene Therapy in Intraocular Hypertension and Glaucoma Treatment.' Please consider relocating them to a more appropriate section."

(3)     Lines 170-171: Please use standard full terms and abbreviations. “OHT/GON (ocular hypertension or glaucoma)” should be stated as "ocular hypertension (OHT)" or "glaucoma-like optic neuropathy (GON)". Please check throughout the manuscript and make the necessary revisions accordingly.

(4)     Table 2: The "target Gene" column needs to be supplemented with specific gene names.

(5)     Line 243: Please revise the format of this title to be consistent with the other titles.

Discussion:

(1)     Lines 366-367: This section might be better placed in the results section.

Materials and Methods:

 

This section may be unnecessary and could be removed.

Comments on the Quality of English Language

This manuscript could benefit a lot from further language editing and revision.

Author Response

Reviewer1

Dear reviewer,

We highly appreciate your thoughtful comments and we hope that, with the changes carried out, our paper ijms-3218327

We have improved the quality of the article according to what you suggested, for which we thank you, as well for your professional evaluation, time and efort! Your suggestions improved our manuscript. In case of any other suggestions, we will try to address it immediately in solving it.

The detailed point-by-point responses to your comments are given below

A good abstract of a review should briefly introduce the background of the review's topic and then focus on summarizing the main content, key findings, viewpoints, and conclusions of the reviewed literature. It should not overly describe the process and results of the literature selection. I strongly suggest the authors read and refer to some high-quality published reviews.

I do the changes

Abstract. Glaucoma is a group of optic neuropathies characterized by degeneration of the ganglion of retinal ganglion cells and loss of their axons in the optic nerve. The only therapies approved for the treatment of glaucoma are topical glaucoma therapy and surgery to lower intraocular pressure. Gene therapy involves inserting, removing, or changing genetic material inside cells to repair or compensate for the loss of a gene's function. Changing the genetic material does not allow increasing the time of overexpression of proteins that will fight a disease, or even the production of new proteins for this purpose. We reviewed the literature review that relates to the use of gene therapy in the treatment of glaucoma and the future directions that this innovation opens up.

Conclusions. With the emergence of gene therapy as a potentially viable way to preserve vision, new ways to manage glaucoma may soon become available. Genomic therapy is a promising therapy for the response of glaucoma patients and has great potential to be widely applied in clinical practice.

Introduction:

 

(1)     Lines 44-50: The sentence “Every cell in our body … may impact our bodies and our health.” is redundant and could be removed for conciseness. This section could be improved by adding information about the surgical treatment options for glaucoma and the associated current challenges.

I do the changes

(2)     The structure of the entire manuscript is not aligned with the standard format for review articles. It is highly recommended to refer to the format and structure of review articles previously published in this journal.

I do the changes

(3)     Line 72: Based on my understanding, Figure 1 depicts the overall history of gene therapy rather than its development specifically in glaucoma treatment. Is the word "in glaucoma" accurate?

I do the changes. I tried to reproduce a history of the appearance of gene therapy, on glaucoma they appeared later and there is still no clear information

Results:

 

• Lines 133-139: The presentation of these results, including Figure 2, follows the format and requirements of a meta-analysis. Please carefully differentiate this and make the necessary revisions accordingly.

I do the changes

 

• Lines 144-165: "The content of these two paragraphs does not align well with subheading 2.1. 'Gene Therapy in Intraocular Hypertension and Glaucoma Treatment.' Please consider relocating them to a more appropriate section."

I do the changes

 

• Lines 170-171: Please use standard full terms and abbreviations. “OHT/GON (ocular hypertension or glaucoma)” should be stated as "ocular hypertension (OHT)" or "glaucoma-like optic neuropathy (GON)". Please check throughout the manuscript and make the necessary revisions accordingly

I do the changes

 

• Table 2: The "target Gene" column needs to be supplemented with specific gene names.

The most studied highly penetrant glaucoma gene is myocilin (a TM-inducible gluco-corticoid response gene). There are more than 70 MYOC mutations, all associated with elevated IOP ranging from mild to severe. Some, such as Gln368X, are commonly asso-ciated with Adult-onset POAG29, while others, such as Pro370Leu, are almost always associated with early onset. Because myocilin mutations are autosomal dominant and most likely cause the disease through a gain-of-function mechanism, the perspective of gene therapy for a patient with a myocilin mutation would be combined atherapy of gene deletion and gene addition. That would involve using siRNA to block the mRNA of the mutant allele and an overexpressed normal gene to increase the levels of just one normal allele. A young patient whose high IOP would be a considerable burden for the rest of his life and who would have a significant chance of becoming blind could be considered for treatment.( Terete Borra´s. Advances in Glaucoma Treatment and Man-agement: Gene Therapy. Glaucoma Gene Therapy. IOVS, Special Issue 2012, Vol. 53, No. 5. 2506-2510.)

 

Three genes associated with glaucoma have been identified within these loci, including myocilin/TIGR (GLC1A), optineurin (GLC1E), and WDR36 (GLC1G).

.

Myocilin (MYOC) was identified by Stone and co-workers in GLC1A locus, which was the first reported locus for POAG located on chromosome 1. In adult POAG populations, the prevalence of myocilin mutations in POAG cases varies between 3 and 5% making it the most common form of inherited glaucoma currently known. Myocilin associated glaucoma is transmitted as an autosomal dominant.

 

OPTN is located in the GLC1E locus on chromosome 10. The phenotype for affected individuals with OPTN variants was remarkable for glaucoma associated with normal IOP, or normal tension glaucoma (NTG), in a large percentage of affected family members.The original report identified OPTN variants in over 16% of open angle glaucoma families.

WDR36 (WD40-repeat 36). Sequence variants in WDR36 gene were reported to cause POAG in 2005. The prevalence of WDR36 sequence variations has been estimated to be between 1.6 and 17% of POAG patients.

Terete Borra´s. Advances in Glaucoma Treatment and Management: Gene Therapy. Glaucoma Gene Therapy. IOVS, Special Issue 2012, Vol. 53, No. 5. 2506-2510.

844. Rand Allinghama,*, Yutao Liub, Douglas J. Rheec. The genetics of primary open-angle glaucoma: A review. Exp Eye Res. 2009 April ; 88(4): 837–844. doi:10.1016/j.exer.2008.11.003.

In addition to the genes described above, over 20 gene variants have been associated with POAG as summarized in Table 2. These include apolipoprotein E (APOE), optic atrophy 1 (OPA1), tumor protein p53 (TP53), tumor necrosis factor (TNF), IL-1, and cytochrome P450 1B1. CYP1B1 has been reported to be associated with early-onset POAG in Spanish, French, and Indian populations (Vasiliou and Gonzalez, 2008).

Vasiliou V, Gonzalez FJ, 2008 Role of CYP1B1 in glaucoma. Annu. Rev. Pharmacol. Toxicol 48, 333358. [PubMed: 17914928]

Variants of OPA1 have been associated with normal tension glaucoma in Japanese and Caucasian populations. OPA1 variants are not associated with glaucoma in Caucasian, African-American, and West African POAG cases with elevated IOP (Liu et al., 2007). Most gene associations with POAG have not been corroborated by other investigators or in other populations.

Lin Y, Liu T, Li J, Yang J, Du Q, Wang J, Yang Y, Liu X, Fan Y, Lu F, Chen Y, Pu Y, Zhang K, He X, Yang Z, 2008 A genome-wide scan maps a novel autosomal dominant juvenile-onset open-angle glaucoma locus to 2p15–16. Mol. Vis 14, 739–744. [PubMed: 18432317]

Liu Y, Schmidt S, Qin X, Gibson J, Munro D, Wiggs JL, Hauser MA, Allingham RR, 2007 No association between OPA1 polymorphisms and primary open-angle glaucoma in three different populations. Mol. Vis 13, 2137–2141. [PubMed: 18079692]

In the table below I will present the type of genes associated with glaucoma

 

Gene	Symbol	Gene name	Genomic location	Glaucoma type	Populations
ANP	Atrial natriuretic polypeptide	1p36.2	108780	POAG	Caucasian
APOE	Apolipoprotein	19q13.2	107741 Neurodegenerative diseases, Alzheimer’s disease	NTG, POA	Japanese, Chinese, Tasmania, French
CDH-1	Cadherin 1	16q22.1	192090 Cell adhesion molecule	POAG	Chinese
CYP1B1	Cytochrome	P450, 1B1 2p22-p21	601771 Tryptophan metabolism	POAG	Indian, French, Spanish
EDNRA	Endothelin receptor	type A 4q31.2	131243 Calcium signaling pathway	NTG	Korean, Japanese
GSTM1	Glutathione S-transferase M1	1p13.3	138350 Glutathione metabolism	POAG	Arabs, Turkish, Estonian
HSPA1A	Heat shock 70 kDa protein 1A	6p21.3	140550 MAPK signaling pathway	POAG, NTG	Japanese
IGF2	Insulin-like growth factor2	11p15.5	147470	POAG	Chinese
IL1α	Interleukin-1 α	2q14	147760 MAPK pathway, apoptosis	POAG	Chinese
IL1β	Interleukin-1 beta	2q14	147720 Apoptosis, MAPK and Toll-like receptor signaling pathway	POAG	Chinese
MTHFR	Methylene-tetrahydrofolate reductase	1p36.3	607093 Folate biosynthesis, methane metabolism	NTG, POAG	Korean, Germany
NOS3	Nitric oxide synthase 3	7q36	163729 Arginine and proline metabolism, calcium and VEGF pathway	POAG with migraine histoRY	Caucasian
OCLM	Oculomedin	1q31.1	604301	POAG	Japanese
OLFM2 2	Olfactomedin	19p13.2		POAG	Japanese
OPA1	Optic atrophy 1	3q28-q29	605290	NTG	Japanese, Caucasian
P21	P21	6p21.2	116899 p53 signaling pathway	POAG	Chinese
PON1	Paraoxonase 1	7q21.3	168820	NTG	Chinese
TAP1	ABC transporter, MHC, 1	6p21.3	170260 ABC transporters	POAG	Chinese
PON1	Paraoxonase	1 7q21.3	168820	NTG	Japanese
TAP1	ABC transporter, MHC, 1	6p21.3	170260 ABC transporters	POAG	Chinese
TLR4	Toll-like receptor 4	9q32-q33	603030 Toll-like receptor signaling pathway	NTG	Japanese
TNFα	Tumor necrosis factor alpha	6p21.3	191160 MAPK and Toll-like receptor pathway, apoptosis	POAG	Japanese, Chinese
TP53	Tumor protein 53	17p13.1	Genomic location MAPK and p53 pathway, apoptosis 191170	POAG	Chinese, Caucasian

 

(5)     Line 243: Please revise the format of this title to be consistent with the other titles.

I do the changes

 

Discussion:

 

(1)     Lines 366-367: This section might be better placed in the results section.

I do the changes

Materials and Methods:

This section may be unnecessary and could be removed.

I remove this sections

 

Thank you so much for your sugestions!

 

Kind regards

 

Nicoleta Anton

Reviewer 2 Report

Comments and Suggestions for Authors

In the review, authors reviewed the papers based on Gene therapy involves the introduction, removal, or alteration of genetic material within cells to repair or compensate for the loss of function in a gene. They have analyzed the literature review that refers to the use of gene therapy in the treatment of glaucoma and the future directions that this innovation opens up. Finally, they conclude that Genomic therapy is a promising treatment for glaucoma patients and holds great potential for widespread application in clinical practice. The review structure and idea look fine and might be attractive to the audiences in the field. However, authors need to solve some minor issues before the publication. 

 

1. Figure 2. (A flowchart of the current survey design, strategy, results, and current studies) is not necessary to be shown since this is a scientific review. Authors need to create figures that focus more on the previous results. 

2.The SIRT1 is the targeted gene. Please list a table for all the targeted gene in the therapy of glaucoma. 

3. Authors claimed that they had selected almost 2284 papers. How did authors handle potential biases in study selection and data extraction? Why only choose papers published between 2015 and 2023. Not 2024 or before 2015. 

4. What are the main barriers to the clinical implementation of gene therapy that were identified in glaucoma therapy?

Comments on the Quality of English Language

minor revision

Author Response

Reviewer 2

Dear reviewer,

We highly appreciate your thoughtful comments and we hope that, with the changes carried out, our paper ijms-3218327

We have improved the quality of the article according to what you suggested, for which we thank you, as well for your professional evaluation, time and efort! Your suggestions improved our manuscript. In case of any other suggestions, we will try to address it immediately in solving it.

The detailed point-by-point responses to your comments are given below

 

 

In the review, authors reviewed the papers based on Gene therapy involves the introduction, removal, or alteration of genetic material within cells to repair or compensate for the loss of function in a gene. They have analyzed the literature review that refers to the use of gene therapy in the treatment of glaucoma and the future directions that this innovation opens up. Finally, they conclude that Genomic therapy is a promising treatment for glaucoma patients and holds great potential for widespread application in clinical practice. The review structure and idea look fine and might be attractive to the audiences in the field. However, authors need to solve some minor issues before the publication.

 

1. Figure 2. (A flowchart of the current survey design, strategy, results, and current studies) is not necessary to be shown since this is a scientific review. Authors need to create figures that focus more on the previous results.

I do the cahnages

2.The SIRT1 is the targeted gene. Please list a table for all the targeted gene in the therapy of glaucoma.

Targeted gene in glaucoma terapy.

I added a table in the text in yellow

3. Authors claimed that they had selected almost 2284 papers. How did authors handle potential biases in study selection and data extraction? Why only choose papers published between 2015 and 2023. Not 2024 or before 2015.

I chose this period because most of the articles were identified in this interval

4. What are the main barriers to the clinical implementation of gene therapy that were identified in glaucoma therapy?

 

As I said at the limits of the study, the main barrier is the lack of knowledge of the safety of off-target gene therapy.

What type of eyelashes will we use and for which type of glaucoma? The safety of using gene therapy for ethical reasons. The number of investigators needed to advance the field of gene therapy for glaucoma is low. The ethical constraints—most importantly, the ethical, legal, and social implications of germline editing—are always controversial and the subject of ongoing debate.

 

Thank you so much for your sugestions!

 

Kind regards

 

Nicoleta Anton

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Abstract:

An excellent abstract for a review article should provide a concise introduction to the background of the topic under examination, swiftly transitioning to a comprehensive summary of the core content, significant discoveries, prevailing viewpoints, and final conclusions drawn from the reviewed literature. It is crucial that the abstract refrains from delving excessively into the specifics of the literature selection process and its results. I urge the authors to consult and draw inspiration from a selection of high-caliber, published reviews. Regrettably, I did not observe the anticipated adjustments in the submitted work.

Results:

 

Lines 216-217: Please use standard full terms and abbreviations. “OHT/GON (ocular hypertension or glaucoma)” should be stated as "ocular hypertension (OHT)" or "glaucoma-like optic neuropathy (GON)". Please check throughout the manuscript and make the necessary revisions accordingly.

Comments on the Quality of English Language

Minor editing of English language required.

Author Response

Round 2

Dear reviewer,

We highly appreciate your thoughtful comments and we hope that, with the changes carried out, our paper ijms-3218327

We have improved the quality of the article according to what you suggested, for which we thank you, as well for your professional evaluation, time and efort! Your suggestions improved our manuscript. In case of any other suggestions, we will try to address it immediately in solving it.

The detailed point-by-point responses to your comments are given below

 

An excellent abstract for a review article should provide a concise introduction to the background of the topic under examination, swiftly transitioning to a comprehensive summary of the core content, significant discoveries, prevailing viewpoints, and final conclusions drawn from the reviewed literature. It is crucial that the abstract refrains from delving excessively into the specifics of the literature selection process and its results. I urge the authors to consult and draw inspiration from a selection of high-caliber, published reviews. Regrettably, I did not observe the anticipated adjustments in the submitted work.

I do the changes! In the text in yellow

Results:

 

 

 

Lines 216-217: Please use standard full terms and abbreviations. “OHT/GON (ocular hypertension or glaucoma)” should be stated as "ocular hypertension (OHT)" or "glaucoma-like optic neuropathy (GON)". Please check throughout the manuscript and make the necessary revisions accordingly.

I do the changes

 

Thank you so much!

 

Kind regards

 

Nicoleta Anton