Table 7.

Targeted Treatment of Spinal Muscular Atrophy

SMA SubtypeTreatmentDosageMechanism
All
subtypes
of SMA		Nusinersen (Spinraza®) 1-4Treatment regimen: 5
1.

Intrathecal loading dose of 12 mg (equivalent dose; 4-5 mL depending on age) every 14 days for a total of 3 loading doses

2.

4th loading dose 30 days after 3rd dose

3.

Then, maintenance doses every 4 mos

Antisense oligonucleotide 6
SMA
type I		Onasemnogene abeparvovec-xioi (Zolgensma®; formerly AVXS-101) 7, 8One-time intravenous injectionGene replacement therapy w/viral delivery of SMN1

Treatments discussed in this table are targeted to address the underlying mechanism of disease causation and not specifically the signs and symptoms experienced by an affected individual (see Table 8).

1.

In the double-blind, sham-controlled Phase III clinical trial of nusinersen in 121 infants with SMA type I, 51% of treated infants showed acquisition of a new motor milestone as assessed by the Hammersmith Infant Neurological Examination (HINE) compared with 0% of controls [Finkel et al 2017].

2.

Further, event-free survival ("event" defined as death or requirement for permanent assisted ventilation) was higher in the nusinersen group than in the control group (hazard ratio 0.53; P=0.005) as was the likelihood of overall survival (hazard ratio 0.37; P=0.004) [Finkel et al 2017].

3.

In the parallel double-blind, sham-controlled, Phase III trial including 126 children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group [Mercuri et al 2018].

4.

The efficacy of treatment with nusinersen in those who already have symptoms is not completely understood [Shorrock et al 2018, Gidaro & Servais 2019].

5.
6.

The antisense oligonucleotide is a single-stranded RNA molecule that is specifically designed to bind to the ISS-N1 regulatory motif in the intron downstream of exon 7 in the SMN2 pre-mMRA [Rigo et al 2014]. Binding at this site promotes inclusion of exon 7, leading to increased full-length SMN mRNA and thus full-length SMN protein.

7.

A Phase I trial in 15 individuals with SMA type I showed event-free survival ("event" = death or need for permanent ventilator assistance) at age 20 months in all 15 compared with only 8% of historical controls [Mendell et al 2017].

8.

Treated individuals showed an improvement in motor milestones and an increase from baseline in objective motor function scales.

From: Spinal Muscular Atrophy

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