Efficacy of Nusinersen Treatment in Type 1, 2, and 3 Spinal Muscular Atrophy: Real-World Data from a Single-Center Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article “Efficacy of Nusinersen ……………….a Single-Center Study by Lemska etal is significant study for SMA community, as the long-term or short- term effects of this drug on patients has not been extensively explored. The Authors present clinical observations and findings that demonstrate that Nusinersen effectiveness in treating SMA significantly enhancing motor function in pediatric patients with SMA type1,2, and 3.

 

Here are the comments:

Minor:

·         Space between line 55-56 between of the and SMN2.

·         I will encourage authors to write gene name in Italics throughout the text ( SMN1, SMN2)

·         Fig.2, n=21, I believe it should be n=23 if data were collected and presented from all 23 patients.

Major comments:

The authors concluded that the small patient cohort and the duration of data collection are significant limitations of the study, which may affect the overall conclusions. While this is a valid point, there are areas where the article could be improved by providing essential context. Notably, the authors did not address whether the study's outcomes correlate with the patients' SMN2 copy numbers. Since SMN2 copy number is a major modifier of the SMN gene, it would be beneficial for the authors to explore whether any of the markers used in this study as endpoints correlate with SMN2 copy numbers. Specifically, it would be informative to see if there are differences in CHOP scores among patients with type 1 SMA compared to those with type 2 or type 3 SMA.Bottom of Form

The authors should clearly indicate that all patients included in this study have a maximum of three copies of the SMN2 gene, as shown in Table 1. Additionally, they should highlight whether patients with higher baseline CHOP scores respond differently to Nusinersen compared to those with lower baseline scores.

Graph3-  data indicate that the CHOP score has not improved for some patient , particularly for those starting with a low baseline score. It would be valuable to explore whether other modifiers, aside from SMN2 copy number—such as SMN hybrid gene structure —have been identified in these cases. Authors should input some of their thoughts on the variability of Nusinersen effect on patients with different SMA types.

Author Response

Comment 1:Space between line 55-56 between of the and SMN2.

I will encourage authors to write gene name in Italics throughout the text ( SMN1, SMN2)

Fig.2, n=21, I believe it should be n=23 if data were collected and presented from all 23 patients.

Respond: It has all been corrected.

Comment 2: The authors concluded that the small patient cohort and the duration of data collection are significant limitations of the study, which may affect the overall conclusions. While this is a valid point, there are areas where the article could be improved by providing essential context. Notably, the authors did not address whether the study's outcomes correlate with the patients' SMN2 copy numbers. Since SMN2 copy number is a major modifier of the SMN gene, it would be beneficial for the authors to explore whether any of the markers used in this study as endpoints correlate with SMN2 copy numbers. Specifically, it would be informative to see if there are differences in CHOP scores among patients with type 1 SMA compared to those with type 2 or type 3 SMA.

The authors should clearly indicate that all patients included in this study have a maximum of three copies of the SMN2 gene, as shown in Table 1. Additionally, they should highlight whether patients with higher baseline CHOP scores respond differently to Nusinersen compared to those with lower baseline scores.

Respond 2: We have carefully considered your suggestions and made the following updates. We have now included an analysis of the potential correlation between SMN2 copy numbers and the outcomes of the study, specifically examining the relationship between SMN2 copy numbers and CHOP INTEND scores.We have also expanded the discussion to include a comparison of CHOP scores between patients with type 1, type 2, and type 3 SMA, highlighting any differences in response to nusinersen.

As suggested, we have explicitly stated that all patients included in this study have a maximum of three copies of the SMN2 gene, as shown in Table 1, to ensure this important detail is clear to the readers.

 We have added a discussion on whether patients with higher baseline CHOP scores exhibited different responses to treatment compared to those with lower baseline scores. This provides additional insight into how baseline functional status may influence therapeutic outcomes.

Comment 3: Graph3-  data indicate that the CHOP score has not improved for some patient , particularly for those starting with a low baseline score. It would be valuable to explore whether other modifiers, aside from SMN2 copy number—such as SMN hybrid gene structure —have been identified in these cases. Authors should input some of their thoughts on the variability of Nusinersen effect on patients with different SMA types.

Respond 3: Thank you for your insightful feedback. I have carefully considered your suggestions and revised the manuscript accordingly. We now include a discussion on potential factors influencing the variability in CHOP INTEND score improvements, particularly for patients with low baseline scores. In addition to SMN2 copy number, we have referenced possible genetic modifiers. Furthermore, we have expanded our discussion on the variability of nusinersen’s effects across different SMA types, considering factors such as disease severity and baseline motor function. 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have described a clinical study conducted in a relatively small and homogenous population of SMA patients to assess the effect of Nusinersen over a 22 month period.  They observed an improvement or stabilization of motor function in all patients in this trial and this study further validates the powerful therapeutic effects of Nusinersen as a treatment for SMA.    

Comments

1. Table 1: A defined table with lines and tabs will be good here for formatting purposes.  To confirm, was the age at start of therapy for all 23 patients approximately 31 months?  

2. Table 1: Could authors use decimal points instead of comma system for the average numbers reported?

3. In the functional assessment section, could authors describe the CHOP-INTEND scoring test and how it is used to obtain clinical assessment scores.  This may further shed light on the variability seen in these scores at baseline in Figure 3.  

4.  Figure 1: Would encourage authors to use a clearer figure (higher quality) as it appears a bit pixelated at 100% zoom. Also, is there a reason these plots are missing error bars? Authors can include error bars or explain why they were excluded.

5.  Between Lines 167-174 and in Figure 2, the authors describe patients who have stabilized, improved and significantly improved and denoted the data in Figure 2.  However, the text does not align with the plots and the color legends on the figure also do not match.  Example: Authors say "Specifically, at 10 months, 65% of patients were stable, 30% improved, and 4% significantly improved."  However if we look at the Figure and the legends, we take away that at 10 months [(33% stabilized (light blue color bar), 62% showed clinically meaningful improvement (dark blue bar) and 5% showed improvement (medium blue bar)].  This is confusing as the text and figures and color legends do not match. Authors should clarify these labels and text for this Figure.  

6.  In Figure 3, is there a correlation between SMN2 copy numbers and baseline CHOP-INTEND scores? Is there a correlation between SMN2 copy numbers and improvements in patients?

7. Authors observed that patients who had worse baseline clinical assessments scored lower on the CHOP-INTEND scale and in these patients the treatment was initiated at a more advanced stage of the disease.  It would be good to highlight for which patients the treatment was initiated later and how much later in terms of age? If all patients were approximately 31 months at the start of treatment, it is not very clear why there is a delay in start of treatments for some patients versus others. Authors should clarify the ages of the group assessed and also when the treatment was started in terms of stage of disease progression.  

8. Could authors comment and cite in the Background on what is known about the therapeutic effects of Nusinersen on SMA Type 0 patients with low SMN2 copy number.  Additionally, why were SMA Type 0 patients not part of this study?  

Author Response

Comment 1. Table 1: A defined table with lines and tabs will be good here for formatting purposes.  To confirm, was the age at start of therapy for all 23 patients approximately 31 months?  

Respond 1: The average age at the start of therapy was 31.24 months for patients with 2 copies, 31.09 months for patients with 3 copies, and 31.09 months for all patients combined. Breaking down the patients into specific groups, those with 2 copies of the SMN2 gene started treatment between 1 and 98 months of age, while patients with 3 copies began treatment between 18 and 86 months of age.

Comment 2. Table 1: Could authors use decimal points instead of comma system for the average numbers reported?

Respond 2: it has been corrected

Comment 3. In the functional assessment section, could authors describe the CHOP-INTEND scoring test and how it is used to obtain clinical assessment scores.  This may further shed light on the variability seen in these scores at baseline in Figure 3. 

Respond 3:  We have added a detailed explanation of the CHOP-INTEND scoring test in the functional assessment section, clarifying how it is used to obtain clinical assessment scores. This addition should help provide further context for the variability seen in baseline scores in Figure 3.

Comment 4.  Figure 1: Would encourage authors to use a clearer figure (higher quality) as it appears a bit pixelated at 100% zoom. Also, is there a reason these plots are missing error bars? Authors can include error bars or explain why they were excluded.

Respond 4: We have replaced Figure 1 with a higher-quality version to improve clarity. Regarding the error bars, we have now included them in the updated figure and provided an explanation in the figure legend to clarify their inclusion.

Comment 5.  Between Lines 167-174 and in Figure 2, the authors describe patients who have stabilized, improved and significantly improved and denoted the data in Figure 2.  However, the text does not align with the plots and the color legends on the figure also do not match.  Example: Authors say "Specifically, at 10 months, 65% of patients were stable, 30% improved, and 4% significantly improved."  However if we look at the Figure and the legends, we take away that at 10 months [(33% stabilized (light blue color bar), 62% showed clinically meaningful improvement (dark blue bar) and 5% showed improvement (medium blue bar)].  This is confusing as the text and figures and color legends do not match. Authors should clarify these labels and text for this Figure.  

Respond 5: It has been corrected 

Comment 6.  In Figure 3, is there a correlation between SMN2 copy numbers and baseline CHOP-INTEND scores? Is there a correlation between SMN2 copy numbers and improvements in patients?

Respond 6: Thank you for your suggestion. We have now included an analysis of the correlation between SMN2 copy numbers and both baseline CHOP-INTEND scores as well as patient improvements. These correlations are discussed in the results section and reflected in the updated Figure 3.

Comment 7. Authors observed that patients who had worse baseline clinical assessments scored lower on the CHOP-INTEND scale and in these patients the treatment was initiated at a more advanced stage of the disease.  It would be good to highlight for which patients the treatment was initiated later and how much later in terms of age? If all patients were approximately 31 months at the start of treatment, it is not very clear why there is a delay in start of treatments for some patients versus others. Authors should clarify the ages of the group assessed and also when the treatment was started in terms of stage of disease progression.  

Respond 7: In out study the average age at the start of therapy was 31.24 months for patients with 2 copies, 31.09 months for patients with 3 copies, and 31.09 months for all patients combined.. However, the variation in baseline clinical assessments and CHOP-INTEND scores reflects differences in disease progression at the time of treatment initiation. Some patients, despite starting treatment at a similar age, may have had more advanced disease progression due to delayed diagnosis or a more aggressive disease course, which contributed to lower baseline scores. We will clarify the ages at which treatment was started and provide further details regarding the stage of disease progression for the different groups in our revised analysis.

Comment 8. Could authors comment and cite in the Background on what is known about the therapeutic effects of Nusinersen on SMA Type 0 patients with low SMN2 copy number.  Additionally, why were SMA Type 0 patients not part of this study? 

Respond 8: Patients with SMA type 0 were not included in our study, as per the current treatment program in Poland. Patients with this type are not eligible for nusinersen therapy due to data suggesting limited effectiveness of the treatment in this group. Instead, SMA type 0 patients receive palliative care

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for thoroughly addressing all the questions with the relevant references. I agree with the findings and comments regarding the correlation between SMA types and the CHOP score. Although the sample size is small, the insights from this study are significant for the SMA community.

Regarding the relationship between SMN2 copy number and phenotype, it’s true to say that it isn’t directly proportional. Often, the SMN2 copy number does not accurately reflect the SMA types, and other modifying factors may also be involved.

4o mini

 

Author Response

Comments 1: 

Thank you for thoroughly addressing all the questions with the relevant references. I agree with the findings and comments regarding the correlation between SMA types and the CHOP score. Although the sample size is small, the insights from this study are significant for the SMA community.

Regarding the relationship between SMN2 copy number and phenotype, it’s true to say that it isn’t directly proportional. Often, the SMN2 copy number does not accurately reflect the SMA types, and other modifying factors may also be involved.

Respond 1: Thank you for this comment 

Reviewer 2 Report

Comments and Suggestions for Authors

Hello, Thank you to the authors for addressing the changes.  

I am still thrown off by potential discrepancy in Figure 2 versus the text for Figure 2.  

Why does it say at 10 months 65% of the patients showed stabilization but the figure legends at the bottom of the plots for 10 months (in very tiny font) says 30% shows stabilization in light blue color (CHOP intend change = 0), 4% shows improvement in medium blue colored (CHOP-intend change +1-3) and 65% is significantly improved in dark blue colored (CHOP-intend >=4).  The bar plots do not correlate with the text between lines 191-202.  It seems that maybe the Figure legend color coding at the bottom of Figure 2 may need to be corrected.  

Minor: The figures (Fig 1, 2 and 4) still show commas instead of decimal points with the numbers on the plots.  

Author Response

Comments1: 

Hello, Thank you to the authors for addressing the changes.  

I am still thrown off by potential discrepancy in Figure 2 versus the text for Figure 2.  

Why does it say at 10 months 65% of the patients showed stabilization but the figure legends at the bottom of the plots for 10 months (in very tiny font) says 30% shows stabilization in light blue color (CHOP intend change = 0), 4% shows improvement in medium blue colored (CHOP-intend change +1-3) and 65% is significantly improved in dark blue colored (CHOP-intend >=4).  The bar plots do not correlate with the text between lines 191-202.  It seems that maybe the Figure legend color coding at the bottom of Figure 2 may need to be corrected.  

Minor: The figures (Fig 1, 2 and 4) still show commas instead of decimal points with the numbers on the plots.  

Respond1: Thank you for your feedback. I have corrected the discrepancy you pointed out between the text and Figure 2.

As for the minor issue with commas instead of decimal points in Figures 1, 2, and 4, unfortunately, I am currently unable to make that adjustment.