Prsentation PowerPoint

1
Towards an understanding of the pathophysiology
and the development of therapeutics in spinal
muscular atrophy
2
SMA dose effect of SMN
type I SMA Gene deletion
Type III SMA Gene conversion
Control
SMN2
SMN2
SMN1
SMN2
SMN1
SMN2
Gene
Protein

• Correlation of SMN protein level with clinical
  severity

3
SMN an ubiquitous multifunctional protein
SMN
control
SMA
?
SMN defect SMA
4
control
mutant

• SMN, an essential protein in various mammalian
  cell types
• SMND7 is not able to compensate for the lack of
  FL-SMN
• MN and skeletal muscle might contribute to motor
  defect
• Correlation of SMN2 copy number with clinical
  severity
• Moderate and late loss of MN (30 reduction)

5
Therapeutic approaches
Upregulation of SMN2 Preventing SMN2 exon 7
Skipping Stabilizing SMND7
SMN2
Genetic basis of SMA
SMN1
Specific pathway
targeted therapeutics ?
Motor neuron and skeletal muscle ?
Pathophysiology ?
non-targeted therapeutics neuroprotection
non-specific degenerative process
Loss of function
Repair or replacement of damaged and lost cells ?
Cell loss
Cellular therapy
SMA
6
Upregulation of SMN2 Preventing SMN2 exon 7
skipping Stabilizing SMND7
SMN2
Genetic basis of SMA
SMN1
Cell system

• Upregulation of SMN2
• Interferon
• Sodium butyrate
• Phenylbutyrate
• Valproic acid

To generate mutant mice suitable for pre-clinical
screening of compounds
7
Therapeutic approaches
Upregulation of SMN2 Preventing SMN2 exon 7
Skipping Stabilizing SMND7
SMN2
Genetic basis of SMA
SMN1
Specific pathway
targeted therapeutics ?
Motor neuron and skeletal muscle ?
Pathophysiology ?
non-targeted therapeutics neuroprotection
non-specific degenerative process
Loss of function
Repair or replacement of damaged and lost cells ?
Cell loss
Cellular therapy
SMA
8
Therapeutic benefit of riluzole or cardiotrophine
1 in a neuronal model of SMA

• Capacity of the SMA mutant neuromuscular system
  to respond to neurotrophic factor.
• Neuroprotection Capacity to attenuate disease
  progression of SMA mice
• Therapeutic intervention in human SMA

9
Therapeutic approaches
Upregulation of SMN2 Preventing SMN2 exon 7
Skipping Stabilizing SMND7
SMN2
Genetic basis of SMA
SMN1
Specific pathway
targeted therapeutics ?
Motor neuron and skeletal muscle ?
Pathophysiology ?
non-targeted therapeutics neuroprotection
non-specific degenerative process
Loss of function
Repair or replacement of damaged and lost cells ?
Cell loss
Cellular therapy
SMA
10
Bone marrow transplantation in mild muscular
mutant mice
5 months

• Aims of the study
• To evaluate the capacity of bone marrow derived
  cells to divide and to differentiate into or fuse
  to skeletal muscle fibers.
• - To test the therapeutic potentialities

11 months
11

• SMN2 a target gene for therapeutics
• Candidates Phenylbutyrate
• Valproic acid
• Neuroprotection a non-targeted therapy
• Candidate Riluzole
• Clinical trials in SMA patients
• SMA pathogenesis Targeted therapeutics ?
• Cell therapy ?

12
Laboratoire de Neurogénétique MoléculaireINSERM,
Université dEvry, E-0223
Judith Melki
Transcriptome analysis Robert Olaso Vandana
Joshi Julien Fernandez
Neuronal model of SMA Jérémie Vitte Jean Marc
Raymackers Vandana Joshi
Therapeutic approaches Nouzha Salah Etienne
Mouisel Gaelle Millet Sabrina Courageot Tony
Frugier Carmen Cifuentes-Diaz Sophie
Nicole Hafedh Haddad
Muscular model of SMA Jérome Lemonnier Bénédicte
Desforges
Animal facility Natacha Roblot Sabrina Soave
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• Acknowledgments
• INSERM
• Association Française contre les Myopathies
• Families of SMA (U.S.A.)
• Université dEvry Val dEssonne
• Conseil Régional
• Fondation Bettencourt Schueller