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Myostatin inhibition in combination with antisense oligonucleotide therapy improves outcomes in spinal muscular atrophy
- Source :
- Journal of Cachexia, Sarcopenia and Muscle, Journal of Cachexia, Sarcopenia and Muscle, Vol 11, Iss 3, Pp 768-782 (2020)
- Publication Year :
- 2020
- Publisher :
- John Wiley and Sons Inc., 2020.
-
Abstract
- BACKGROUND Spinal muscular atrophy (SMA) is caused by genetic defects in the survival motor neuron 1 (SMN1) gene that lead to SMN deficiency. Different SMN‐restoring therapies substantially prolong survival and function in transgenic mice of SMA. However, these therapies do not entirely prevent muscle atrophy and restore function completely. To further improve the outcome, we explored the potential of a combinatorial therapy by modulating SMN production and muscle‐enhancing approach as a novel therapeutic strategy for SMA. METHODS The experiments were performed in a mouse model of severe SMA. A previously reported 25‐mer morpholino antisense oligomer PMO25 was used to restore SMN expression. The adeno‐associated virus‐mediated expression of myostatin propeptide was used to block the myostatin pathway. Newborn SMA mice were treated with a single subcutaneous injection of 40 μg/g (therapeutic dose) or 10 μg/g (low‐dose) PMO25 on its own or together with systemic delivery of a single dose of adeno‐associated virus‐mediated expression of myostatin propeptide. The multiple effects of myostatin inhibition on survival, skeletal muscle phenotype, motor function, neuromuscular junction maturation, and proprioceptive afferences were evaluated. RESULTS We show that myostatin inhibition acts synergistically with SMN‐restoring antisense therapy in SMA mice treated with the higher therapeutic dose PMO25 (40 μg/g), by increasing not only body weight (21% increase in male mice at Day 40), muscle mass (38% increase), and fibre size (35% increase in tibialis anterior muscle in 3 month female SMA mice), but also motor function and physical performance as measured in hanging wire test (two‐fold increase in time score) and treadmill exercise test (two‐fold increase in running distance). In SMA mice treated with low‐dose PMO25 (10 μg/g), the early application of myostatin inhibition prolongs survival (40% increase), improves neuromuscular junction maturation (50% increase) and innervation (30% increase), and increases both the size of sensory neurons in dorsal root ganglia (60% increase) and the preservation of proprioceptive synapses in the spinal cord (30% increase). CONCLUSIONS These data suggest that myostatin inhibition, in addition to the well‐known effect on muscle mass, can also positively influence the sensory neural circuits that may enhance motor neurons function. While the availability of the antisense drug Spinraza for SMA and other SMN‐enhancing therapies has provided unprecedented improvement in SMA patients, there are still unmet needs in these patients. Our study provides further rationale for considering myostatin inhibitors as a therapeutic intervention in SMA patients, in combination with SMN‐restoring drugs.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
lcsh:Diseases of the musculoskeletal system
Survival of motor neuron 1 gene
Combinatorial therapy
government.form_of_government
SMN1
Myostatin
lcsh:QM1-695
03 medical and health sciences
0302 clinical medicine
Physiology (medical)
Internal medicine
medicine
Orthopedics and Sports Medicine
Antisense oligonucleotide
Antisense therapy
Myostatin inhibition
biology
business.industry
Myostatin propeptide
Skeletal muscle
Spinal muscular atrophy
lcsh:Human anatomy
Original Articles
Motor neuron
medicine.disease
SMA
Muscle atrophy
030104 developmental biology
Endocrinology
medicine.anatomical_structure
030220 oncology & carcinogenesis
biology.protein
government
Original Article
medicine.symptom
lcsh:RC925-935
business
Adeno‐associated virus
Subjects
Details
- Language :
- English
- ISSN :
- 21906009 and 21905991
- Volume :
- 11
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Journal of Cachexia, Sarcopenia and Muscle
- Accession number :
- edsair.doi.dedup.....9ca9e5fa6de609536313061b7873c33a