What is Spinal Muscular Atrophy (SMA)?
 

August 7th is observed annually as International Spinal Muscular Atrophy (SMA) Awareness Day.

Spinal Muscular Atrophy (SMA) is an autosomal recessive inherited neuromuscular disorder primarily caused by inactivating mutations in the Survival Motor Neuron 1 (SMN1) gene. This leads to degeneration of motor neurons in the anterior horn of the spinal cord, resulting in progressive proximal muscle weakness and atrophy in the limbs. The disease not only affects motor function but may also involve multiple systems, including respiratory, digestive, and skeletal systems.

The incidence of SMA is approximately 1 in 6,000 to 1 in 10,000 live births, making it one of the leading genetic causes of infant mortality. Based on age of onset and clinical manifestations, SMA is classified into types I through IV, with type I being the most severe and typically leading to death before the age of two.
 

Pathogenesis
 

The pathogenesis of SMA is primarily associated with mutations or deletions of the Survival Motor Neuron 1 (SMN1) gene. Located at 5q13.2, the SMN1 gene encodes the SMN protein, which is widely expressed in cells and involved in various cellular processes, including the assembly of small nuclear ribonucleoproteins (snRNPs). Due to gene mutations or deletions, the expression level of SMN protein is significantly reduced, leading to selective death of motor neurons. Additionally, the human genome contains a highly homologous SMN2 gene. However, due to a point mutation in its transcript, most SMN2 transcripts lack exon 7, producing an unstable and functionally impaired SMNΔ7 protein. The copy number of the SMN2 gene is inversely correlated with the severity of SMA.
 

 

(Image: PubMed)

Gene Therapy
 

● SMN1 Gene Replacement Therapy: Involves delivering a functional copy of the SMN1 gene into patients using viral vectors (e.g., AAV9) to restore SMN protein expression. AAV9 has been shown to effectively transduce motor neurons and lead to phenotypic correction when administered systemically in neonatal SMA mice or via intracerebroventricular (ICV) delivery. The self-developed GC101 adeno-associated virus injection by Beijing Genecradle Pharmaceutical Technology Co., Ltd. utilizes a single intrathecal administration to enable SMN1 gene expression in motor neurons. Single-dose GC101 gene therapy has demonstrated significant efficacy in treating type II and III SMA.

● SMN2 Gene Modification Therapy: Aims to increase SMN levels by modulating SMN2 splicing using antisense oligonucleotides (ASOs). ASOs are designed to base-pair with specific splicing regulatory sequences, promoting the inclusion of exon 7 and restoring SMN expression. In SMA, a key target is the Intronic Splicing Silencer N1 (ISS-N1) located within SMN2 intron 7. Blocking this element can significantly enhance the stability and function of the SMN protein.
 

Mouse Models
 

● SMN2 Mice: Generated by knocking out the mouse Smn gene and inserting the human SMN2 gene. These mice exhibit rapidly progressive neuromuscular degeneration and severe motor dysfunction, dying before postnatal day 7 (P7). They are often referred to as "severe" models.

● SMNΔ7 Mice: Generated by introducing the SMNΔ7 gene on a background of two SMN2 copies (SMN−/− ; SMN2+/+ ; SMNΔ7+/+). They have a slightly extended lifespan (around 14 days), exhibit severe neuromuscular symptoms, and more closely mimic the molecular pathology of human SMA patients.

● SMN2B/− Mice: Carry three nucleotide mutations introduced into the exon 7 splicing enhancer region, leading to moderate levels of SMN protein expression. They exhibit clearer neuromuscular phenotypes and longer survival, making them suitable for studying the pathological mechanisms of mild SMA.

● SMNF7/Δ7; NSE-Cre+ Mice: Feature neuron-specific knockout. They have a lifespan of 25-31 days.

● SMNF7/Δ7; HSA-Cre+ Mice: Feature skeletal muscle-specific knockout. They have a lifespan of 33 days.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various SMA mouse models according to client needs, such as SMN2 mice, SMNΔ7 mice, SMN2B/− mice, SMNF7/Δ7; NSE-Cre+ mice, and SMNF7/Δ7; HSA-Cre+ mice. We welcome inquiries!

 

References:

[1] Huang Wenchen, Qu Yujin. Research Progress in the Treatment of Spinal Muscular Atrophy. International Journal of Pediatrics, 2024, 51(02): 119-123. DOI: 10.3760/cma.j.issn.1673-4408.2024.02.012

[2] Van Alstyne M, Pellizzoni L. Advances in modeling and treating spinal muscular atrophy. Curr Opin Neurol. 2016 Oct;29(5):549-56. doi: 10.1097/WCO.0000000000000368. PMID: 27472505; PMCID: PMC5074385.

[3] Sleigh JN, Gillingwater TH, Talbot K. The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. Dis Model Mech. 2011 Jul;4(4):457-67. doi: 10.1242/dmm.007245. PMID: 21708901; PMCID: PMC3124050.

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