Studying the effect of gene therapy on spinal muscular atrophy (SMA) phenotype

Studying the effect of gene therapy on spinal muscular atrophy (SMA) phenotype
Niloofar torkzadeh,^1,* Mozhgan shirazi,²
1. Department of Biochemistry, Islamic Azad University, Falavarjan, Iran
2. Department of Biology, Scince and Reserch Branch, Islamic Azad, university, tehran, iran
Introduction: Spinal muscular atrophy(SMA) is an autosomal recessive disorder caused by degeneration of alpha motor neurons in the anterior horn of the spinal cord. The characteristic symptoms are hypotonia, muscular atrophy and weakness of proximal muscles predominatly affecting the lower extremities. Before therapies were developed, SMA was classified into three main types (typesΙ-Ш) based on the age of onset and achieved motor milestones. The emergence of additional phenotypes broadened this classification to include congenital(type 0) and adult onset(typeΙѴ).
Methods: We reviwed about 22 article were conducted frome 2018 to 2023 in the word and iran. We searched some key words such as spinal muscular atrophy, SMA threatment, gene therapy, phenotype_genotype SMA in sciencedirect, Elsevier, pubmed and SID.
Results: The disease typically presents in infancy or childhood, leading to severe physical disability. The weakness is usually symmetrical, more proximal than distal, the legs are more affected than the arms and there is relative sparing of the diaphragm and extraocular and facial muscles. Despite relative sparing of the diaphragm respiratory insufficiency is an important complication of SMA5q. deep tendon reflexes are generally absent or diminished. There is a brood spectrum of clinical severity with phenotypes divided into types 1-4, determined principally by maximal motor milestone attained and age of onset. The differential diagnosis includes X-linked infantile SMA with arthrogrryposis(XL_SMA), SMA due to mitochondrial dysfunction, SMA with pontocerebellar hypoplasia (SMA-PCH/PCH1) and SMA with respiratory distress (SMA RD). SMA RD( or HMN type ΙѴ) is probably the second most commonly encountered pediatric from of SMA due to mutations in IGHBP2. This includes lower extremity predominant SMA type1 and 2 caused by heterozygous mutations in DYNIH1 and BLCD2 respectively. SMN1(also called SMN where T stands for telomere spans 20kb and lies in the telomeric portion of an inverted duplication of 500kb a DNA architecture prone to rearrangements and deletions. First thought to have 8 exons both SMN1 and SMN2 contain 9 exons that encode the 294 amino acide protein, survival of motor neuron(SMN) . the exons are numbered 1, 2a, 2b,3,4,5,6,7 and 8. The stop codon for SMN occurs in exin 7 and exon 8 is left untranslated. SMN1 and SMN2 vary 8 nucleotides 5 of which are intronic and 3 of which occur in the last 3 exins. Of the differences only a C to T transition in SMN2 exon7 (specifically C.840 C/T) falls in a coding region and disrupts an exonic splice enhancer in exon7. Recurrent variant have been found in exone3 and 6 making these two exon hot spots for small mutations and missense mutations respectively. Exon6 codes for a domain in the protein which plays a role in protein oligomerization and those patients with exon 6 missense mutations have decreased SMN protein self oligomerization capacity. Neurophysiological findings in patients with SMA provide support to these observations with alteration in spinal H reflexes spinal circuity and ion channel function in motor nerves identified of therapeutic relevance increasing the excitability of motor circuits through the pharmacological inhibition of K channels ameliorated SMA in animal models. although several viral vectors including retroviruses, lentiviruses adenoviruses and herpesviruse have been considered for neurological disease indication, there has been a recent coalescence around adeno viruses( AAVs) because the are nonpathogenic and can transduce neurons. AAVs establish themselves as persistently expressing episomes with little incorporation into the host genome and can theoretically persist indefinitely in nondividing cells such as neurons. Onasemnogene abeparvovec is the next new drug that was introduced clinical practice after nusineren. The drug was developed for SMN gene (more precisely, full length SMN cDNA) transfer. Onasemnogene abeparvovec is an scAAV9 vector based drug crossing the blood brain barrier. AAV vectors do not integrate into DNA.
Conclusion: SMA syndrome should not be confused with nutcracker syndrome (which can be an association), also a superior mesenteric artery compression disorder, where the SMA compresses the left renal vein, although some authors use the terms interchangeably. SMA results from the of SMN1 but retention its paralog SMN2 copy number can modulate disease severity in SMA SMN2 copy number is becoming an inclusion criterion for many clinical trials for SMA.
Keywords: Spinal Muscular Atrophy, SMA threatment, Gene therapy, Phenotype_genotype SMA,Genetic