Nusinersen: A Novel Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) encompasses a group of autosomal recessively inherited degenerative neuromuscular disorders. They range in severity from neonatal onset with rapidly progressive weakness and early mortality (SMA-1), to onset in infancy (SMA-2), to adolescent/adult onset with indolent clinical course (SMA-3/-4). SMA patients share mutations in the survival motor neuron (SMN) gene; variations in clinical phenotypes are attributable to copy numbers of the closely related SMN2 gene. In December 2016, the US Food and Drug Administration (FDA) approved nusinersen (Spinraza, Biogen, Cambridge, MA) to treat SMA. Nusinersen, an antisense oligonucleotide, is administered directly into cerebrospinal fluid. It alters SMN2 pre-RNA splicing so exon 7 is included, increasing expression of functional SMN protein. Although nusinersen was FDA approved for treatment of all forms of SMA, the initial clinical trials were limited to patients up to age 14 years, diagnosed with SMA-1,-2, -3, not on mechanical ventilation support. Two subsequent phase 3 trials were completed for SMA-1 and SMA-2/-3 and demonstrated improved motor milestones and event-free survival, better than expected based on natural history studies. Efficacy assessments for patients receiving nusinersen are based on serial assessments of performance on age-appropriate standardized motor scales. Treatment requires complex financial and logistics because of the very high drug cost, intrathecal administration, and medical fragility of the patients. Treatment implementation also engenders ethical considerations related to cost, insurance coverage, limited clinical data on groups of patients not in clinical trials, and questions of duration of treatment. Nusinersen has been integrated into the treatment of many SMA patients.

Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

“…Intrathecal drug administration is useful when the disease target is on the surface of the brain or spinal cord, such as meningeal carcinoma (Larson et al, 2015), or drug delivery to the motor neurons near the surface of the lumbar spinal cord. Nusinersen (Spinraza ) is a phosphorothioate antisense oligonucleotide that is FDA approved for the treatment of SMA (Neil and Bisaccia, 2019). The drug is injected directly into the lumbar CSF, where the affected motor neurons within the anterior horn of the spinal cord sit just 1-2 mm from the CSF bathing the surface of the spinal cord (Bican et al, 2013).…”

Antisense Oligonucleotide in LNA-Gapmer Design Targeting TGFBR2—A Key Single Gene Target for Safe and Effective Inhibition of TGFβ Signaling

“…ASOs can be applied into anatomically defined regions, where they may be locally contained in the area of application [2,3]. Thus, Antisense technology is gaining upcoming relevance in the field of therapeutic applications [2,[4][5][6][7][8]. A recent example is Nusinersen, a successful FDA-approved ASO and the first compound for treating spinal muscular atrophy [7][8][9][10][11].…”

Therapeutic targeting of alternative splicing

“…Degeneracja motoneuronów zaburza stymulację nerwową mięśni poprzecznie prążkowanych, co prowadzi do postępującego osłabienia mięśni, ogólnego upośledzenia motoryki oraz narastających trudności w oddychaniu. Wyróżnia się pięć typów SMA (tabela 1), które znacząco różnią się przebiegiem [17,18]. Około 60% pacjentów cierpi na SMA typu 1.…”

“…Ponadto, pierścień rybozy został zmodyfikowany w pozycji 2' przez wprowadzenie ugrupowania 2-metoksyetylowego, co niweluje rozpoznawanie dupleksu utworzonego przez nusinersen i pre-mRNA SMN2 przez enzym rybonukleazę H, co skutkowałoby rozkładem pre-mRNA wcześniejsze podanie leku może skuteczniej niwelować lub opóźniać objawy choroby, znacząco zwiększając szanse bardziej prawidłowego rozwoju. Choć badanie nie zostało jeszcze zakończone, zaobserwowano już u dzieci pozytywny wpływ na rozwój motoryczny, w tym uzyskanie zdolności do samodzielnego siedzenia czy zdolności chodzenia, które nie mogłyby rozwinąć się u nieleczonych dzieci z SMA typu 1/2 [18].…”