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. 2021 Jul;8(7):1495-1501.
doi: 10.1002/acn3.51377. Epub 2021 May 15.

Increased systemic HSP70B levels in spinal muscular atrophy infants

Eric J Eichelberger  1 , Christiano R R Alves  1 , Ren Zhang  1 , Marco Petrillo  2 , Patrick Cullen  2 , Wildon Farwell  2 , Jessica A Hurt  2 , John F Staropoli  2   3 , Kathryn J Swoboda  1
Affiliations

Increased systemic HSP70B levels in spinal muscular atrophy infants

Eric J Eichelberger et al. Ann Clin Transl Neurol. 2021 Jul.

Abstract

Despite newly available treatments for spinal muscular atrophy (SMA), novel circulating biomarkers are still critically necessary to track SMA progression and therapeutic response. To identify potential biomarkers, we performed whole-blood RNA sequencing analysis in SMA type 1 subjects under 1 year old and age-matched healthy controls. Our analysis revealed the Heat Shock Protein Family A Member 7 (HSPA7)/heat shock 70kDa protein 7 (HSP70B) as a novel candidate biomarker to track SMA progression early in life. Changes in circulating HSP70B protein levels were associated with changes in circulating neurofilament levels in SMA newborns and infants. Future studies will determine whether HSP70B levels respond to molecular therapies.

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Conflict of interest statement

EJE, CRRA, and RZ report no conflict of interest. MP, WF, PC, and JAH are employees of Biogen and hold stock/stock options in Biogen. JFS was a employer at Biogen at the time the work was performed and holds stock/stock options in Biogen; he is now employed at Vertex Pharmaceuticals, Boston. KJS is on the scientific advisory board for Cure SMA and is a consultant for Biogen, Roche and AveXis. KJS receives clinical trial funding from AveXis and Biogen.

Figures

FIGURE 1
FIGURE 1
RNA sequencing reveals increased HSP70B mRNA levels in the whole blood of SMA Infants. (A) Negative binomial normalized read counts of SMN1 and SMN2 genes in SMA versus healthy controls. Green indicates control subjects, while blue indicates SMA subjects. (B) Volcano plot comparing SMA and control subjects. (C) Heatmap plot of normalized counts for genes with p < 0.01 and an absolute value of log2 fold change > 1.2. (D) Normalized counts of SMA and healthy patients for differentially expressed genes with FDR < 0.2. Green indicates control subjects, while blue indicates SMA subjects. (E) Quantitative RT‐qPCR for HSPA7 mRNA levels. p = 0.02. (F) HSPA7 mRNA levels in a cohort of SMA patients divided into symptomatic SMA subjects with only two SMN2 copies, symptomatic SMA subjects with three SMN2 copies, and pre‐symptomatic SMA subjects with three SMN2 copies. p = 0.01 and p = 0.003 when comparing pre‐symptomatic SMA subjects with symptomatic SMA subjects with only two SMN2 copies and symptomatic SMA subjects with three SMN2 copies, respectively.
FIGURE 2
FIGURE 2
Increased systemic intron retention in SMA infants. (A) Comparison between SMA and controls for total intron retention in the whole blood (p < 0.001). (B‐C) Pie charts showing the percentage of introns more retained in SMA or control subjects. (D) Comparison between SMA and controls for U12 intron retention in the whole blood (P < 0.001). (E‐F) Pie charts showing the percentage of U12 introns more retained in SMA or control subjects. Individual values indicate each intron retained in individual samples. PSI: percentage spliced‐in values.
FIGURE 3
FIGURE 3
Association between HSPA7 protein levels and neurofilament concentrations. (A) Association between serum HSP70B protein levels and neurofilament concentrations. Kendall rank correlation coefficient revealed p = 0.018, with a Spearman r value of 0.37. (B) Division of samples in two groups based on low and high neurofilament concentrations in SMA patients. (C) HSP70B protein levels in samples previously divided based on neurofilament levels. p = 0.01 between groups.
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