Impact of Disease Severity and Disease-Modifying Therapies on Myostatin Levels in SMA Patients

Abstract

Clinical trials with treatments inhibiting myostatin pathways to increase muscle mass are currently ongoing in spinal muscular atrophy. Given evidence of potential myostatin pathway downregulation in Spinal Muscular Atrophy (SMA), restoring sufficient myostatin levels using disease-modifying treatments (DMTs) might arguably be necessary prior to considering myostatin inhibitors as an add-on treatment. This retrospective study assessed pre-treatment myostatin and follistatin levels' correlation with disease severity and explored their alteration by disease-modifying treatment in SMA. We retrospectively collected clinical characteristics, motor scores, and mysotatin and follistatin levels between 2018 and 2020 in 25 Belgian patients with SMA (SMA1 (n = 13), SMA2 (n = 6), SMA 3 (n = 6)) and treated by nusinersen. Data were collected prior to treatment and after 2, 6, 10, 18, and 30 months of treatment. Myostatin levels correlated with patients' age, weight, SMA type, and motor function before treatment initiation. After treatment, we observed correlations between myostatin levels and some motor function scores (i.e., MFM32, HFMSE, 6MWT), but no major effect of nusinersen on myostatin or follistatin levels over time. In conclusion, further research is needed to determine if DMTs can impact myostatin and follistatin levels in SMA, and how this could potentially influence patient selection for ongoing myostatin inhibitor trials.

Keywords: FSTN; GDF8; clinical trials; disease-modifying therapies; follisatin; myostatin; nusinersen; spinal muscular atrophy.

Figure 2

Correlation of myostatin levels with motor scores and follistatin blood levels in nusinersen-naïve patients. Graphs showing the significant correlation of myostatin with (A) MFM32, (B) CHOP-INTEND, (C) HFMSE, (D) 6MWT. No significant correlation was observed between myostatin and left grip score (E), right grip score (F), HINE-2 (G), and follistatin (H). Significant results are indicated by an asterisk (*).

Figure 1

Myostatin levels per SMA type and correlation with age and weight in nusinersen-naïve patients. (A) Boxplot displaying myostatin levels for SMA types with outliers indicated by dots. (B) Significant correlation between myostatin levels, (B) age, and (C) weight within SMA1 and SMA2. Significant results are indicated by an asterisk (*) and dots indicate outliers.

Figure 3

Change in myostatin and follistatin levels from baseline in treated patients. (A) Change in myostatin (blue) and follistatin (red) levels over a period of 2 months with treatment by nusinersen (N = 10); (B) over a period of 6 months with treatment by nusinersen (N = 11); (C) over a period of 10 months with treatment by nusinersen (N = 9); (D) over a period of 18 months with treatment by nusinersen (N = 10). Full dots indicate overlapping points. Horizontal lines illustrate mean values.

Figure 4

Association between myostatin and motor scores over time. (A) Line graph displaying the trend in myostatin levels following up to 30 months of treatment with nusinersen (n = 25). (B) Arrow graph showing the association between myostatin and MFM32, (C) HFMSE, and (D) 6MWT from baseline to 18 months of treatment with nusinersen. Arrow indicates temporality. SMA types 1, 2, and 3 are indicated in blue, beige, and red, respectively. Significant results are indicated by an asterisk (*).