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Spinal Muscular Atrophy (SMA)
Skeletal Muscle and Neuromuscular Junction (NMJ) Components

Identifying diverse modalities including small molecules and regenerative progenitor cells to restore functional skeletal muscle and neuromuscular junction in SMA

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Prevalence/ Incidence

  • Muscle atrophy and loss of motor neurons in the anterior horn of the spinal chord to yield muscular weakness
    • Proximal muscles are most severely affected
    • Muscle weakness is the most common symptom
    • Cognitive and emotional development are unaffected
    • Orphan drug designation by the FDA
    • After CF, the most common autosomal recessive inherited disorder
  • SMA was granted orphan drug designation by the FDA
  • 1 in 40 people are carriers
  • 1 in 6,000-10,000 children born with SMA
    • Estimated number of patients in US is ~9,000

SMA is Caused by Defects in the SMN1 gene

Associated with mutations in the survival of motor neuron gene (SMN1)

  • 2 forms of SMN gene on each allele: a telomeric (SMN1) and centromeric form (SMN2)
  • Transcription of the SMN1 gene produces full-length messenger RNA that encode the SMN protein
  • The SMN2 gene is identical to the SMN1 gene except for a C to T substitution at position 840 to exclude exon 7 during transcription.
  • The resultant truncated protein is not function and rapidly degrades.
  • The exclusion of exon 7 is not complete, a small fraction of total mRNA transcript (~10-20%) encodes full-length, functional SMN
  • Copy number of SMN2 in SMA patients ranges from 1-5, there is a positive correlation between SMN2 copy number and milder phenotypes

SMA Varies in Severity

SMA has a continuous spectrum of symptoms that ranges from very severe to mild across the four classifications of SMA types

Type Severity Age of onset Life expectancy Characteristics
(Werdnig-Hoffman disease)
Severe 0-6 months <2 years Quick and unexpected onset (“floppy baby syndrome”). Rapid motor neuron death causes respiratory complications that are frequent cause of death. Unless placed on mechanical ventilation, SMA type 1 patients do not live past 2 years.
II Intermediate 7-18 months >2 years Child is never able to stand and walk but are able to maintain a sitting position at some point. Weakness usually observed between 6-18 months. Muscle weakness is progressive and respiratory system is a major concern.
(Kugelberg-Welander disease)
Mild >18 months Adult Juvenile form that usually manifests after 1 year of age. Patients are able to walk without support at some time, by may loss this ability. Respiratory involvement is less noticeable and life expectancy is normal or near normal.
(adult form)
Mildest Second and third decade Adult Adult-onset form usually manifests in the third decade of life with gradual weakening of the muscles. Life expectancy is normal.

Developmental delay in SMA muscle

MYOCEA: ‘primary screening edge’


hPSC model of SMA: developmental delays in myoblast differentiation

SMA myoblasts show reductions in MHC expression and the number of MyoD+ cells


Developmental Delay: Quantitation of MHC and MyoD expression in
SMA vs. unaffected myoblasts


Developmental delay in iPSC-derived myoblasts from SMA Type 1 lines


SMA Type 2 and 3 iPSC lines show a similar developmental delay


SMA Type 2 and 3 iPSC lines show a similar developmental delay

SMA Type 2 and 3 show a developmental delay phenotype


MYOCEA: Summary of EC50s for top compounds

Signaling Networks Modulated

Compound Pathway MYOCEA102
MyoD EC50
MyoD EC50
MYO1 Network 1 15 nM 6 nM 7 nM 3 nM
MYO2 Network 2 13 nM 6 nM 640 nM <1 nM
MYO3 Network 3 55 nM 1.2 uM
MYO4 Integrin inhibitor 120 nM 770 nM 4 uM
MYO5 Actin polymerization
10 nM 950 nM
MYO6 Src inhibitor 40 nM 120 nM
MYO7 LIM kinase and
ROCK inhibitor
310 nM 1.1 uM
MYO8 Network 4 110 nM 40 nM 100 nM 250 nM
MYO9 Network 5 30 nM 740 nM

MYOCEA: SMA Secondary Assays

Capitalizing on reported clinical pathologies

Published SMA phenotype Secondary assay
Decreased muscle function Nuclei/myofiber
Fusion index
Myotube size/diameter
Autophagy Activation of Ubiquitin pathway
Expression of p62, beclin, LC3
RFP-GFP-LC3B Autophagy Sensor
Mitochondrial function Bioenergetics: Seahorse mito stress test
Mitochondrial DNA content
Mitochondrial membrane polarization
Mitochondrial complex protein expression
Neuromuscular Junction NMJ co-culture
Agrin induced AcH reorganization
Motor neuron function

MYOCEA: Hits rescue bioenergetic phenotype in SMA myoblasts

Pharmacological response (100 nM and 1 uM)


Secondary assays: SMA myoblasts have a mitochondrial membrane polarization defect

Fig1. JC-10:
‧ Much more soluble than JC-1
‧ Monomer: green = depolarized mitochondria
‧ Trimer: red = intact, polarized mitochondria

Fig2. All SMA lines tested show mitochondrial hypopolarization in their resting state


JC-10 staining of mito membrane polarization in myoblasts


MYOCEA: SMA, Nanostring™ Assay

Treatment of SMA myoblasts with hits brings gene expression profile closer to unaffected cells


SMA myoblasts have a glycolytic deficit


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