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Research Article
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Short-duration splice promoting compound enables a tunable mouse model of spinal muscular atrophy

Anne Rietz, Kevin J Hodgetts, Hrvoje Lusic, Kevin M Quist, View ORCID ProfileErkan Y Osman, View ORCID ProfileChristian L Lorson, View ORCID ProfileElliot J Androphy  Correspondence email
Anne Rietz
1Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
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Kevin J Hodgetts
2Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA
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Hrvoje Lusic
2Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA, USA
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Kevin M Quist
1Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
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Erkan Y Osman
3Department of Veterinary Pathobiology, Bond Life Sciences Center, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
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Christian L Lorson
3Department of Veterinary Pathobiology, Bond Life Sciences Center, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA
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  • ORCID record for Christian L Lorson
Elliot J Androphy
1Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • ORCID record for Elliot J Androphy
  • For correspondence: eandro@iu.edu
Published 24 November 2020. DOI: 10.26508/lsa.202000889
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  • Figure S1.
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    Figure S1.

    NVS-SM2 increases SMN2-luc in SMN2 reporter cells. (A) Response of indicated doses of NVS-SM2 on SMN2 luciferase (red) and Renilla luciferase (black) after 24 h incubation. NVS-SM2 increased SMN2-luc with an EC50 of 100 nM. (B) SMN protein expression in total brain lysate of untreated PND7 neonatal FVB/N, het and severe 5058 spinal muscular atrophy mice. SMN 2F1 antibody detects only human SMN protein, whereas MANSMA 6 detects human and mouse. SMN 2F1 antibody does not detect a SMN protein band in FVB/N control mice confirming specificity towards human SMN protein. Data expressed as SEM.

  • Figure 1.
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    Figure 1. NVS-SM2 increases survival motor neuron (SMN) protein in severe 5058 spinal muscular atrophy (SMA) and control Het mice.

    Mice were injected s.c. with 1 mg/kg NVS-SM2 or vehicle starting PND 2 daily until PND 6. Mice were euthanized and tissues harvested on PND 7. (A, B, C) Human SMN protein levels were analyzed in brain (A), spinal cord (B), and muscle (C) tissues via immunoblotting. SMN protein was normalized to actin and tubulin. Each lane represents tissue from an individual mouse. SMA represents the severe 5058 SMA mice, which express the human SMN2 transgene, and Het mice are their littermates, expressing both human and mouse SMN.

  • Figure S2.
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    Figure S2. Quantification of survival motor neuron expression normalized to actin.

    Healthy Het and spinal muscular atrophy mice were injected s.c. with 1 mg/kg NVS-SM2 (NVS) or vehicle (VH) starting PND2 daily till PND 6. Mice were euthanized and tissues harvested on PND7. (A, B) Human survival motor neuron protein levels were quantified in brain (A) and spinal cord (B) by normalization to actin. A P-value of P < 0.05 was taken as statistically significant. * indicates levels of significance (*P < 0.05, **P < 0.01, ***P < 0.001) and # indicates P < 0.05 for spinal muscular atrophy-VH versus Het-VH. Each treatment group comprises an n = 3. Data expressed as SEM and were analyzed using one-way ANOVA with Bonferroni post hoc analysis.

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    Figure 2. Effect of different doses of NVS-SM2 on severe 5058 spinal muscular atrophy (SMA) mice.

    (A) Kaplan–Meier survival curves of severe 5058 SMA mice s.c. treated with vehicle (n = 7) or 0.1 (n = 4) and 1 mg/kg (n = 5) NVS-SM2 daily until PND 15 and then every other day until PND 30 (A). Mantel–Cox test was used to analyze survival differences between NVS-treated and SMA mice and P-values are presented in the legend. (B, C, D) Mice were monitored for body weights (B) and tail length (C, D). Data expressed as SEM.

  • Figure S3.
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    Figure S3.

    Ratio of tail length to body weight. (A, B) Tail length normalized to body weight of severe spinal muscular atrophy mice versus healthy het control siblings and (B) PND8 severe spinal muscular atrophy mice treated s.c. with 1 mg/kg compared with healthy Het control. PND, postnatal day. Data expressed as SEM.

  • Figure 3.
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    Figure 3. Effect of 3-d treatments with different dosages of NVS-SM2 on severe 5058 spinal muscular atrophy (SMA) mice.

    Severe 5058 SMA mice were treated on PND 2, PND 3 and PND 4 s.c. or orally (p.o.) with the indicated doses of NVS-SM2. (A) Kaplan–Meier survival curve of severe 5058 SMA mice s.c. treated with 0.1 (n = 6), 0.5 (n = 6), and 1 mg/kg (n = 6) NVS-SM2 or orally with 1 mg/kg NVS-SM2 (n = 4) and untreated SMA mice (n = 10). Mantel–Cox test was used to analyze survival differences between NVS-treated and SMA mice and P-values are presented in the legend. (B, C, D) Mice were monitored for body weights (B) and tail length (C) to determine the tail length: body weight ratio (D). (E) Pen test time of 0.5 mg/kg NVS-SM2–treated mice in comparison to Het mice (E). Data expressed as SEM.

  • Figure 4.
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    Figure 4. Impact of NVS-SM2 treatment on severe 5058 spinal muscular atrophy (SMA) mice survival after 2-d treatments.

    Severe SMA mice were treated on PND 2 and PND 3 with the indicated doses of NVS-SM2. (A) Kaplan–Meier survival curve of severe 5058 SMA mice treated s.c. with 0.1 mg/kg NVS-SM2 (n = 5) on PND 2 and PND 3 in comparison to untreated SMA mice (n = 6). Mantel–Cox test was used to analyze survival differences between NVS-treated and SMA mice and P-values are presented in the legend. (B) Mice were monitored for body weights. Data expressed as SEM.

  • Figure 5.
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    Figure 5. Effect of 3-d treatments with NVS-SM2 on SMN∆7 mice.

    SMN∆7 mice were treated on PND 2, PND 3, and PND 4 s.c. with 1 mg/kg NVS-SM2. (A, B) Kaplan–Meier survival curve (A) and body weights (B) of untreated (n = 10) and NVS-SM2 (n = 4)–treated SMN∆7 mice. Mantel–Cox test was used to analyze survival differences between NVS-treated and untreated SMA mice and P-values are presented in the legend. Data expressed as SEM.

  • Figure 6.
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    Figure 6. Effect of late treatment of severe spinal muscular atrophy (SMA) (5058) mice with NVS-SM2.

    Animals were treated starting on PND 6 (A, n = 3) or PND 8 (B, n = 14) s.c. with 1 mg/kg NVS-SM2. (A, B) Kaplan–Meier survival curves. PND 8–treated SMA mice were further separated into non-survivors (n = 8) and survivors (n = 6) groups. Mantel–Cox test was used to analyze survival differences between NVS-treated and SMA mice and P-values are presented in the legend. (C, D) PND 8–treated severe 5058 SMA mice were monitored for body weights (C) and tail lengths (D). Data expressed as SEM.

  • Figure 7.
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    Figure 7. Effect of late treatment of NVS-SM2 in severe 5058 spinal muscular atrophy (SMA) mice.

    (A) Spleen weights of NVS-SM2–treated severe 5058 SMA mice at PND 110 in comparison to healthy Het control mice are not different (A). (B) Average body weight at PND 8 of the treated NVS-SM2 mice separated into the survivors and non-survivors groups are not different (B). Data expressed as SEM and analyzed using Student’s unpaired t test, a P-value of 0.05 was taken as significant. ns indicates nonsignificance.

  • Figure 8.
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    Figure 8. Survival motor neuron (SMN) protein levels in NVS-SM2–treated severe 5058 spinal muscular atrophy (SMA) mice at PND 110 compared to healthy Het control mice.

    (A, B, C, D) Immunoblot of human SMN and housekeeping proteins at PND 110 in Het (n = 4) and NVS-SMN2 PND 8–treated severe SMA 5058 mice (n = 5) in brain (A, B) and spinal cord (C, D). SMN protein was normalized to housekeeping proteins (B, D). Each lane represents tissue from an individual mouse. Data expressed as SEM and analyzed using Student's unpaired t test, a P-value of 0.05 was taken as significant.

Supplementary Materials

  • Figures
  • Video 1

    Healthy het control siblings (n = 2, no markings on the tail) and NVS-SM2–treated severe 5058 SMA mice (n = 3, black markings on the tail or no tail) on PND 94. Starting on PND 2, mice were injected s.c. with NVS-SM2 (1 mg/kg) for 30 d and then the treatment was stopped. Download video

  • Video 2

    Healthy Het control siblings (n = 2, no markings on the tail) and PND 8–treated NVS-SM2 severe 5058 SMA mouse (n = 1, black markings on the tail) on PND 104. Starting on PND 8, mouse was treated with NVS-SM2 (1 mg/kg) s.c. four times a week. Download video

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A pharmacologically tunable SMA mouse model
Anne Rietz, Kevin J Hodgetts, Hrvoje Lusic, Kevin M Quist, Erkan Y Osman, Christian L Lorson, Elliot J Androphy
Life Science Alliance Nov 2020, 4 (1) e202000889; DOI: 10.26508/lsa.202000889

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A pharmacologically tunable SMA mouse model
Anne Rietz, Kevin J Hodgetts, Hrvoje Lusic, Kevin M Quist, Erkan Y Osman, Christian L Lorson, Elliot J Androphy
Life Science Alliance Nov 2020, 4 (1) e202000889; DOI: 10.26508/lsa.202000889
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Volume 4, No. 1
January 2021
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