Nusinersen is the first treatment available for children with spinal muscular atrophy (SMA). Before its approval in 2016, the U.S. Food and Drug Administration had not approved the use of any drug for SMA treatment.1 While the introduction of this new drug marks significant progress in SMA therapy and provides new potential for those living with the disease, it also poses new challenges, including practical challenges like determining how best to deliver the drug to SMA patients. A new study, published in Pediatric Radiology, has helped to identify a potentially advantageous way of administering nusinersen to adolescents with SMA.2
SMA occurs because of a mutation to the survival motor neuron 1 (SMN1) gene, which results in reduced levels of SMN protein. Another survival motor neuron gene, SMN2, allows people with SMA to survive if it produces enough SMN protein.3 Also known as Spinraza, nusinersen is an antisense oligonucleotide that corrects the splicing of SMN2 mRNA so that the gene produces more of the SMN protein, increasing levels of the protein in the central nervous system.4
Nusinersen is generally delivered through intrathecal injections, or injections into the spinal canal.5 Unfortunately, the nature of SMA often makes these injections technically difficult because of the spinal abnormalities like scoliosis that occur in many SMA patients.6 Often, SMA patients need corrective surgery for the spine and then wear orthopedic devices that hinder access to the parts of the spine where injections would ideally occur.7 This access challenge led to high dropout and exclusion rates in early clinical trials for nusinersen.8 Now, researchers have provided a potential solution to this technical problem.
The team of researchers in Texas investigated the potential for delivering nusinersen through an ultrasound-guided cervical puncture, which is often used for drug delivery in other diseases, such as cancer.2,9 By analyzing 14 of these procedures, delivered to 2 male and 2 female patients ranging in age from 12 to 19, the researchers concluded that this route of administration should be added to the options that healthcare providers consider when initiating nusinersen therapy in adolescents. Through their evaluation, the scientists found that all 14 procedures were technically successful and none were associated with major complications. In 2 of the 14 administrations, the patient experienced headaches, but these headaches resolved within 24 hours.
According to the researchers, this cervical route for the delivery of nusinersen in SMA patients does not only seem technically feasible and well-tolerated, but it may confer additional advantages over other methods of administration as well.2 For instance, the technique allows for real-time ultrasound guidance, and it can be performed with local anesthesia. Avoiding general anesthesia is ideal, as it is also associated with unique complications in SMA patients, including respiratory difficulties.
Further research into the use and delivery of nusinersen in SMA patients will likely provide more information on the best ways to administer this therapy to SMA patients. It may too elucidate distinct advantages of specific administration routes for different SMA patient populations.
1. Shorrock HK, Gillingwater TH, Groen EJN. Overview of Current Drugs and Molecules in Development for Spinal Muscular Atrophy Therapy. Drugs. 2018;78(3):293-305. doi:10.1007/s40265-018-0868-8
2. Ortiz CB, Kukreja KU, Lotze TE, Chau A. Ultrasound-guided cervical puncture for nusinersen administration in adolescents. Pediatr Radiol. 2019;49(1):136-140. doi:10.1007/s00247-018-4240-7
3. Corti S, Nizzardo M, Simone C, et al. Genetic correction of human induced pluripotent stem cells from patients with spinal muscular atrophy. Sci Transl Med. 2012;4(165):165ra162. doi:10.1126/scitranslmed.3004108
4. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol. 2007;5(4):e73. doi:10.1371/journal.pbio.0050073
5. Hache M, Swoboda KJ, Sethna N, et al. Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. J Child Neurol. 2016;31(7):899-906. doi:10.1177/0883073815627882
6. Sucato DJ. Spine deformity in spinal muscular atrophy. J Bone Joint Surg Am. 2007;89 Suppl 1:148-154. doi:10.2106/JBJS.F.00293
7. Phillips DP, Roye DPJ, Farcy JP, Leet A, Shelton YA. Surgical treatment of scoliosis in a spinal muscular atrophy population. Spine (Phila Pa 1976). 1990;15(9):942-945.
8. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet (London, England). 2016;388(10063):3017-3026. doi:10.1016/S0140-6736(16)31408-8
9. Yousem DM, Gujar SK. Are C1-2 punctures for routine cervical myelography below the standard of care? AJNR Am J Neuroradiol. 2009;30(7):1360-1363. doi:10.3174/ajnr.A1594