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Human Growth Hormone Increases SMN Expression and Survival in Severe Spinal Muscular Atrophy Mouse Model
Duncan MacKenzie1, Fahad Shamim1, Kevin Mongeon1
1Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
Insights
Human growth hormone (HGH) shows promise for treating spinal muscular atrophy (SMA). HGH boosts survival motor neuron (SMN) protein levels, improving disease outcomes in SMA mouse models.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Spinal muscular atrophy (SMA) is a severe inherited neuromuscular disorder caused by low levels of functional survival motor neuron (SMN) protein.
- SMA leads to progressive muscle atrophy and respiratory failure, representing a significant cause of infant mortality.
Purpose of the Study:
- To investigate the potential of human growth hormone (HGH) as a therapeutic agent for SMA by upregulating SMN protein levels.
- To assess HGH's impact on the STAT5 signaling pathway, previously shown to influence SMN levels.
Main Methods:
- HGH was administered to NT2 cells and transgenic SMA mouse models.
- STAT5 pathway activation and SMN protein levels were measured.
- Disease phenotype and survival rates in SMA mice were evaluated.
Main Results:
- HGH treatment activated the STAT5 pathway and significantly increased SMN protein levels in both cell cultures and mouse models.
- HGH administration improved the disease phenotype and extended survival in severe SMA mouse models.
Conclusions:
- The findings support the activation of the STAT5 pathway as a viable therapeutic strategy for SMA.
- Human growth hormone (HGH) emerges as a promising candidate for SMA treatment.
Background:
Autosomal recessive spinal muscle atrophy (SMA) is characterized by the loss of α motor neurons resulting in progressive muscle loss and respiratory failure. SMA is one of the most common inherited causes of infant death with a carrier frequency of 1 in 50 and a calculated prevalence of about 1 in 11,000 live births in the US. The low amount of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene causes SMA.
Objective:
A potential treatment strategy for SMA is to upregulate levels of SMN protein originating from the paralog SMN2 gene compensating in part for the absence of the SMN1 gene. Our group has previously shown that activation of the STAT5 pathway by lactation hormone prolactin (PRL) increased SMN levels, improved motor function and enhanced survival in a severe SMA mouse model. Given that human growth hormone (HGH) is also known to activate the STAT5 signalling pathway and is already used extensively in clinical settings, we thus elected to assess its impact on SMN levels.
Methods And Results:
Administration of HGH in NT2 cells activated STAT5 pathway which resulted into significant induction in SMN protein levels. Furthermore, systemic administration of HGH to transgenic SMA mice induced SMN protein levels in the brain and spinal cord samples. Critically, HGH treatment improved disease phenotype and increased survival in two severe SMA mouse models.
Conclusions:
Our results confirm earlier work suggesting STAT5 pathway activators as potential therapeutic compounds for the treatment of SMA and identify HGH as one such promising agent.
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