• A new study of the effect of the gene therapy (SMN2 gene) for ALS and SMA (Spinal Muscular Atrophy)
  • Niloofar Torkzadeh,1,* Mozhgan Shirazi2,2
    1. Department of Biochemistry, Islamic Azad University, Falavarjan, Iran
    2. Department of Biology, Science and Research branch, Islamic Azad University, Tehran, Iran


  • Introduction: SMA is the clinical classified into four phenotypes on the basis of age of onset and motor function achieved. Two almost identical SMN genes are present on chromosome 5q13: the telomeric or SMN1 gene, which is the spinal muscular atrophy determining gene and the centromeric or SMN2 gene the coding sequence of SMN2 differs from that of SMN1 by single nucleotide (84oc>t), which does not alter the aminoacidic sequence but results in alternative splicing of exon 7. Due to the alternative splicing of exon7, SMN2 genes produce a reduced amount of full-length lacking exon 710% to 50% SMN which give raise to a truncated and unstable protein. About 95% of patients have a homozygous disruption of SMN1 due to deletion or gene conversion of SMN1 to SMN2.
  • Methods: We reviewed about 22 articles were conducted from 2018 to 2025 in the world and Iran. We searched some key words such as spinal muscular atrophy, neuroscience, gene therapy, ALS, phenotype-genotype SMA in ScienceDirect, Elsevier, PubMed and Sid
  • Results: SMA is currently divided into five subtypes: type 0 (the most severe form with onset in the prenatal period and development of severe respiratory problems after birth), type Ι (Werdnig Hoffmann disease, a severe form with onset before 6 months of age and the inability to sit unsupported), type Π (Dubowitz disease, an intermediate form with onset before 18 months of age and the ability to sit unaided, but not to stand or walk), type Ш (Kugelberg Welander disease, a mild form with onset after 18 month of age and the ability to stand and walk unabated), type ΙѴ (the mildest form with onset after 30 years of age). Mechanisms involving the alternation of SMN2 splicing by restoring the inclusion of exon7 are targeted by gene therapy currently use in the treatment of SMA. Of the positive regulators of SMN2 splicing, the best characterized splice factor at present are serine arginine rich splice factor (SRSF1) and transformer beta homolog2 (that bind directly to the exon7 splicing, enhancing regions of se1 and se2). Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and the SRC related substrate at mitosis 68 are reported to have inhibitory activity on SMN2 splicing. Exon exclusion can occur by binding the intronic N1 silencer sequence ISSN1 or the hnRNP A1 sequence to se2. The c6u substitution also causes A1 or sam68 hnRNA to bind se1 in place of the positive regulator. Other factor involved in splicing regulation include srp30c, TDP43, TIA, hnRNPQ and hnRNPG. Another cause of exon 7 skipping may be the increased activity of a regulatory sequence located at the 3 end of exon7, called terminal stem loop2. In 2009, Foust et al. reported that an intravenously injected self-complementary AAV9 vector crossed the blood brain barrier and entered cells of the central nervous system. The AAV9 vector targeted cells within the central nervous system. The concept of SCAAV will be explained later in this review. The next year, the authors reported that the scAAVg vector carrying SMN gene (scAAV9-smn) was injected into the facial vein of neonatal SMA model mice on the first day after birth resulting in prolonged survival of one of the treated mice. TLL2 acts as activator of myostatin (MSTN, growth differentiation factor8) which inhibits skeletal muscle growth. The TLL2 point mutation identified in the milder sibling are predicted to reduce MSTN activation. (Neuritin is an SMN interacting protein in neurons which promotes neurite out growth overex pression of NRN1 in various animal models for SMA showed increased motor neurite out growth. Yener et al recently showed elevated NRN, mRNA levels in a mildly affected sibling within a discordant family. The second drug approved for SMA therapy is zolgensma (AVXS101), onasemnogene abeparvovec. In 2019 the fad authorized the use of zolgensma for children under 2 years of age whose diagnosis of SMA has been confirmed by genetic tests. In uses a non-replicating adeno associated virus capsid (scAAVg) to deliver transgene under a ubiquitous promoter to motor neuron cell. It is noteworthy that in contrast to nusinersen zolgensma crosses the blood brain barrier and one administration per 1 h intravenous infusion is sufficient for the systemic expression of the SMA protein
  • Conclusion: Adeno associated virus (AAV) vectors have also been used to deliver ASOS to the central nervous system by intrathecal infusion. Passini et al have shown a very efficient transfer rate of oligonucleotides, with increased expression smn f1 in mice models and provided evidence that this route of administration has a higher efficiency than systemic delivery. SMA is a devastating genetic neuromuscular disorder, leading to significant infant and childhood mortality and morbidity. The most common mutation in homozygous disruption of SMN1 and causative genes implicate altered RNA processing axonal transport and protein degradation.
  • Keywords: spinal muscular atrophy, neuroscience, gene therapy, ALS, phenotype-genotype SMA