Nusinersen for the treatment of spinal muscular atrophy

ABSTRACT

Introduction: Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder characterized by loss of spinal motor neurons leading to muscle weakness. This review article focuses on a novel antisense oligonucleotide treatment, first ever approved for SMA (nusinersen, Spinraza^TM) and describes the exciting journey from early ASO clinical trials to regulatory approval of the first ever known effective treatment for SMA.

Areas covered: This article reviews the results of the published open label nusinersen studies in infants and children, and briefly covers the preliminary findings of the recently completed but as yet unpublished nusinersen–sham controlled trials, as well as the presymptomatic nusinersen trial known as Nurture. Clinical use of nusinersen is also reviewed.

Expert commentary: Collectively, the studies show improvement in motor function across SMA of all types, including SMA type 3. Best motor response was observed with early treatment; presymptomatic treatment prevented disease manifestations. Nusinersen was found to be safe and well tolerated across all age groups studied. Nusinersen has irrevocably altered the natural history of SMA and allowed for the first time children to transition between SMA types. Nusinersen should be considered as standard of care for the treatment of SMA of all types.

KEYWORDS:

• Spinal muscular atrophy (SMA)
• Nusinersen (Spinraza TM)
• Antisense oligonucleotide (ASO)
• SMN1/SMN2
• intrathecal injections
• infantile onset SMA
• later onset SMA
• clinical trials
• sham-control studies
• open label studies

ACKNOWLEDGMENTS

The author also wishes to acknowledge principle investigators who participated in the various studies discussed herein including:

CS3A:  Richard S Finkel, MD (Nemours Children’s Hospital, Orlando, FL), Jiri Vajsar, MD (University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada), John W Day, MD (Stanford University School of Medicine, Stanford, CA);

CS2/C12:  Katherine Swoboda, MD, (University of Utah, UT) Basil Darras, MD (Boston Children’s Hospital, Boston MA) Susan Iannaccone, MD  (University of Texas Southwest, Dallas, TX).

CS3B:  Richard S Finkel, MD (Nemours Children’s Hospital, Orlando, FL), Nancy Kuntz, MD (Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA), Eugenio Mercuri, MD (Università Cattolica del Sacro Cuore, Rome, Italy), Francesco Muntoni, MD (University College London, London, UK), Basil Darras, MD (Boston Children’s Hospital, Boston MA), Topaloglu Haluk (Hacettepe University, Ankara, Turkey) and other Endear Study Group members.

CS4: Eugenio Mercuri, MD (Università Cattolica del Sacro Cuore, Rome, Italy); Richard S Finkel, MD (Nemours Children’s Hospital, Orlando, FL); Jan Kirschner, MD (Universtatsklinikum Freiburg, Freiburg, Germany) Nancy Kuntz, MD (Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA) Basil Darras, MD (Boston Children’s Hospital, Boston MA) Perry Shieh (UCLA School of Medicine, Los Angeles, CA, USA) Kayoko Saito, MD (Tokyo Women’s Medical University, Tokyo) and other CHERISH Study Group Members.

Information resources

Sumner CJ. Therapeutics development for spinal muscular atrophy. NeuroRx. 2006;3:235–45.

Wang CH, Finkel RS, Bertini ES, et al. Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007 22:1027–49.

Howell MD, Singh NN, Singh RN. Advances in therapeutic development for spinal muscular atrophy. Future Med Chem. 2014;6:1081–99.

Declaration of interest

CA Chiriboga has served on the advisory board of Ionis, Biogen, Avexis, and Roche and has received funding from NIH, Ionis, Biogen, Roche Pharmaceuticals, and Avexis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.