Spinraza affects peripheral motor neurons despite the blood-brain barrier
the verdict
REFUTED
the evidence says no
refutedsupported
the weight of evidence
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Published literature confirms that Spinraza (nusinersen) is unable to cross the blood-brain barrier, which is why it must be administered via intrathecal injection rather than systemically to reach target motor neurons.
Spinal muscular atrophy (SMA), the most frequent genetic cause of infant mortality, is caused by deletion of the survival of motor neuron 1 (SMN1) gene. Humans have a paralogous gene SMN2 that produces the same SMN protein; however, only ~10% of functional SMN protein is produced as ~90% of SMN2 transcripts lack exon 7 due to splicing of this essential exon. Synthetic DNA-like molecules called antisense oligonucleotides (AOs) are promising agents for the treatment of SMA. Spinraza, the first approved drug for SMA, is an AO that binds to an intronic splicing silencer region in SMN2 transcripts and restores the production of full-length SMN2 (FL-SMN2). SMA is a multi-organ disorder affecting the heart, liver, muscle, and spleen; however, Spinraza is injected intrathecally to avoid renal toxicity and therefore can treat only motor neurons. Therefore, a compound providing effective yet safe delivery of AOs to the central nervous system (CNS) and body-wide organs is needed to prevent SMA-related morbidity and death. Here, we demonstrate that a novel peptide-conjugated antisense morpholino oligomer DG9-PMO is safe and improves the efficacy of the AO treatment in a mouse model of SMA. DG9 was conjugated to a safe AO called phosphorodiamidate morpholino oligomer (PMO) targeting SMN2. We subcutaneously injected SMA mice with DG9-PMO on postnatal day 0 (PD0). DG9-PMO-treated mice had significantly increased FL-SMN2 expression by reaching the CNS as well as the peripheral tissues. DG9-P
s on chromosome 5 of the SMN1 gene ( 1 ). The main clinical features of patients were progressive muscle weakness and muscle atrophy resulting from the degeneration of motor neurons in the anterior horn of spinal cord ( 2 ). The prevalence of SMA is 1–2 in 100,000 in developing countries ( 3 ). Furthermore, SMA is the most fatal genetic disease in children under 2 years of age; SMA affects the respiratory system, with respiratory failure being the most common cause of death ( 4 ). Nusinersen was the first approved disease-modifying treatment for SMA. It is an antisense oligonucleotide drug, which modifies pre-mRNA splicing to promote inclusion of SMN2 exon 7, which increases production of full-length SMN proteins ( 5 ). In clinical trials, Nusinersen was demonstrated to significantly improve both motor function and overall survival ( 6 ). As Nusinersen is unable to penetrate the blood-brain barrier, Nusinerson needs to be administered by repeat intrathecal injection at an injection dose of 12 mg (5 ml) each time. Typically, the first three doses are given 14 days apart, and a fourth dose given 30 days after the third dose. After this, maintenance therapy should be administered every 4 months, usually for more than 5 years ( 7 ). Platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT) and urine protein should be measured before administration. Common adverse events of Nusinersen include respiratory infections and constipation, though some patients develop thrombocytopenia and coagulopathy, increasing their risk of nephrotoxicity ( 8 ). Nusinersen is proven to have significant clinical benefits for SMA in children, improving motor function.
Clinical use of a drug is associated with not only curative effect, but also the safety of the drug, which affects its clinical application. However, till date, there are no meta-analysis studies on the adverse events of nociception in children and adolescents. Therefore, this study used meta-analysis to
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