Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletion or mutation of the SMN1 gene. It is characterized by a progressive loss of motor neurons resulting in muscle weakness. The disease affects 1 in 11,000 live births and before the era of treatment SMA was a leading genetic cause of mortality in infants. Recently, disease modifying therapies have been introduced in clinical practice. They include intrathecal and oral antisense oligonucleotides binding to pre-mRNA of SMN2 gene and increasing the translation of fully functional SMN protein as well as SMN1 gene replacement therapy. Onasemnogene abeparvovec uses the adeno-associated virus 9 (AAV9) vector to deliver the SMN1 gene. Phase 1 and phase 3 clinical trials showed that a single administration of onasemnogene abeparvovec resulted in improvement of motor functions in the majority of infants with SMA. Currently, phase 3 trials in SMA1 and SMA2 patients, as well as presymptomatic infants diagnosed with SMA, are ongoing. The drug was approved for medical use in the US in 2019, and in Japan and the European Union in 2020. Thus, first real-world data on efficacy and safety of onasemnogene abeparvovec in SMA patients are available.
Highlights
Specialty section: This article was submitted to Experimental Therapeutics, a section of the journal Frontiers in Neurology
In contrast to other therapies approved for Spinal Muscular Atrophy (SMA) treatment, nusinersen, and risdiplam, which alter the splicing of SMN2 gene, onasemnogene abeparvovec is designed to deliver a full-length functional copy of the human SMN1 gene
Clinical trials with onasemnogene abeparvovec in human subjects started after animal studies had shown that systemically delivered self-complementary associated virus 9 (AAV9) crossed the blood-brain barrier, and achieved high levels of neuronal transduction in SMA murine models [44, 49]
Summary
Recent years brought a breakthrough change in the management and prognosis in SMA [27]. In 2021, risdiplam (RO7034067), which is an SMN2 mRNA splicing modifier was approved by the FDA and EMA for the treatment of SMA in patients 2 months of age and older, with a clinical diagnosis of type 1, type 2 or type 3 SMA or with one to four SMN2 copies [39]. In a double-blind, placebo-controlled SUNFISH study in people aged 2–25 years with SMA types 2 or 3 risdiplam improved the score of Motor Function Measure 32 at 12 months (SUNFISH Study data). In a double-blind, placebo-controlled SUNFISH study in people aged 2–25 years with SMA types 2 or 3 risdiplam improved the score of Motor Function Measure 32 at 12 months (SUNFISH Study data1) Another oral molecule SMN2 increasing generation of fulllength SMN2 mRNA and functional SMN protein by modulating SMN2 splicing, branaplam (LMI070) is studied in SMA type 1 infants. EMA limited the use of the medication for patients who weigh 2.6–21.0 kg
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