d'Ydewalle C, Ramos DM, Pyles NJ, Ng SY, Gorz M, Pilato CM, Ling K, Kong L, Ward AJ, Rubin LL, Rigo F, Bennett CF, Sumner CJ. The Antisense Transcript SMN-AS1 Regulates SMN Expression and Is a Novel Therapeutic Target for Spinal Muscular Atrophy.
Neuron. 2017 Jan 4;93(1):66-79. doi: 10.1016/j.neuron.2016.11.033. Epub 2016 Dec 22.
Submitted by Shan (Sarah) Cen, MD, PhD and Leigh Maria K. Ramos-Platt, MD, News Science Editorial Board
Spinal muscular atrophy (SMA) is a rare but devastating neuromuscular disorder characterized by loss of motor neurons in the spinal cord and progressive muscle weakness. SMA is inherited in an autosomal recessive manner. It is caused by a SMN1 gene mutation with a result of insufficient expression of survival motor neuron (SMN) protein. Therefore, SMA therapeutics development efforts have focused on identifying strategies to increase SMN expression.
In this study, d'Ydewalle and colleagues led by Dr. Sumner in Johns Hopkins Medical Institute identified a long non-coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, which is abundant in neurons. Its function is repressing SMN expression during transcription. Therefore, targeted degradation of SMN-AS1 with antisense oligonucleotides (ASOs) increases SMN expression. They showed this effect in patient-derived cells, cultured neurons, and the mouse central nervous system. In addition, they found that SMN-AS1 ASOs delivered together with SMN2 splice-switching oligonucleotides additively increase SMN expression and improve survival of severe SMA mice.
: SMA is the most common genetic cause of infant death. It is exciting news that in December 2016, Nusinersen, marketed as Spinraza™
, became the first approved drug to treat SMA while several other compounds remain in clinical trials. Nusinersen is also an antisense olionucleotide (ASO) that modulates the alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene, thus increasing the level of SMN protein in the CNS through intrathecal injection. This significance of this study is that it is the first proof of concept that targeting a lncRNA to transcriptionally activate SMN2 combined with SMN2 splicing modification can ameliorate SMA. It demonstrates the effectiveness of treating SMA using this regimen. More importantly, this study shows the potential of using combinatorial ASOs for the treatment of neurogenetic disorders in general.
Finkel R; Chiriboga C; Vajsar J; Day J; Montes J et al. Treatment of Infantile-onset Spinal Muscular Atrophy With Nusinersen: a Phase 2, Open-label, Dose Escalation Study
, the Lancet,
Vol 388, December 2016.
Finkel and colleagues, published their findings on a phase 2 open label, dose escalation of 20 infants diagnosed with SMA 1 (confirmed by genetic evaluation to have deletion or mutation in both SMN1 genes) who received the intrathecal anti-sense oligonucleotide, Nusinersen. This study assessed the safety, tolerability, pharmokinetics (particularly if the medication made it to the target tissue, the anterior horn cells), and clinical efficacy over the course of approximately 32 months. The patients were all between the ages of 3 weeks to 7 months and diagnosed between 3 weeks and 6 months of age. 20 participants received different doses on days 1, 15, and 85 (four patients received 6 mg and the remainder 16 received 12 mg). On day 253 and every 4 months subsequently, all patients received 12 mg doses. One patient died before reaching day 253 and two afterwards (a total of three patients died). The efficacy of the drug was assessed using multiple parameters including change from baseline on two motor scales (HINE and the CHOP-INTEND). Endpoints of survival, tracheostomy, daily ventilation, and death were compared to published natural history data. Biopsies of the central nervous system of patients who died were compared to four untreated SMA patients and three patients without SMA who died. Adverse events were evaluated. The 19 patients who survived past day 253 were included in the analysis. 16/19 patients had improvements from their baseline scores with 13/16 attaining the ability to grasp, 9/16 attaining kicking, 1/16 attaining sitting, 6/16 attaining head control, rolling, five standing, two crawling, and two walking. While all participants experiences adverse events, 77 which were considered serious, the researchers did not feel that these were related to the medication. Rather, these events were associated with the medical fragility of patients with infantile SMA. Nusinersen was found in the motor neurons of the patients who had passed away. There was also a deviation of the Kaplan-Meier curve of ventilation free survival in patients who received Nusinersen compared to the natural history data. These findings support the safety, tolerability, clinical efficacy, and ability to reach the target tissue of Nusinersen.
Since the approval of Nusinersen for chromosome 5 SMA 1,2,3, and 4, questions have been asked whether the medication is efficacious. These findings on this study are in concordance with other Nusinersen studies – including double blind placebo controlled studies. This study does demonstrate a clinical efficacy of the medication.
About the AANEM News Science Editorial Board
The board helps to highlight significant, timely science news items for AANEM members. It reviews articles in journals and websites, identifies newsworthy items in the field, and writes article summaries.