Spinal Muscular Atrophy (SMA)

What is Spinal Muscular Atrophy?

Spinal muscular atrophy (SMA) is an inherited disorder characterized by degeneration of the anterior horn cells, muscle atrophy, and weakness. The most common SMA is caused by mutations in the 5q13 survival of the motor neuron (SMN1) gene.

Molecular Genetics and Etiology

There are two almost identical SMN genes on chromosome 5q13: the telomeric or SMN1 gene, which determines spinal muscle atrophy, and the centromeric or SMN2 gene. The coding sequence of SMN2 differs from that of SMN1 by one nucleotide (840C > T), which does not change the aminoacidic sequence but leads to the selective splicing of exon 7. Due to the selective splicing of exon 7, SMN2 genes produce a reduced number of full-length transcripts (SMN-fl) and protein, and a variable amount of mRNA lacking exon 7 (10% to 50%, SMN-del7) which results in a truncated and unstable protein. About 95% of patients have interrupted SMN1 homozygosity due to deletion or gene conversion of SMN1 to SMN2. About 3% of affected individuals are compound heterozygotes for missing one SMN1 allele and subtle intragenic mutations.

There are two hypotheses in the pathogenesis of SMA: (a) SMN is involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs) and mRNA splicing; (b) SMN has a motor neuron-specific function and is independent of the assembly of snRNPs.

Methods for SMA Genetic Testing

• Linkage analysis
• Polymerase chain reaction/single-strand conformation polymorphism
• PCR-RFLP assay (SMN1 deletion assay)
• Quantitative SMN gene dosage analyses
• SMN1 small intragenic (or subtle) mutation analysis
• Prenatal SMA genetic testing
• Preimplantation SMA genetic testing
• Haploid analysis

Therapeutic Strategies

• Pharmacological Therapies

Several mechanisms have been targeted in SMA drug trials such as neuroprotective drugs to rescue motorneurons (as riluzole), creatine to improve energy metabolism, and albuterol for its anabolic properties and the molecular effect on SMN2 gene expression. Preliminary therapeutic efforts have been dominated by drugs targeting the modulation of SMN2 pre-mRNA splicing, aimed at increasing SMN-fl levels, or the enhancement of SMN2 promoter activity.

• Gene Therapy

In a series of experiments, self-complementary AAV8-hSMN was injected at birth intrathecally into the CNS of SMA-like mice, increasing the median life span of affected animals up to 50 days, compared with 15 days for untreated controls. Adeno-associated virus (AAV) vectors have also been used to deliver ASOs to the central nervous system by intrathecal infusion.

• Stem Cell Therapy

Stem cell approaches offer promise as a cellular replacement strategy in the treatment of SMA and it is currently receiving considerable attention. Cell replacement may be achieved by transplantation of stem cell-derived cells which have undergone maturation in vitro, or by activation of endogenous stem cells in the CNS.

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