2017 Top Stories in Neurology: New Therapeutics in Spinal Muscular Atrophy
Spinal muscular atrophy (SMA), one of the most common inheritable neuromuscular diseases, is caused by a homozygous deletion or mutation in the survival motor neuron-1 (SMN1) gene, resulting in decreased protein expression and motor neuron degeneration in the spinal cord and brainstem, clinically manifested with a varying degree of progressive skeletal and respiratory muscle weakness with muscular atrophy. The infantile subtype (SMA1; known as Werdnig–Hoffman disease) accounts for 60% of all cases and leads to death or confinement to mechanical ventilation by the age of 2 years. Humans have a backup copy, the SMN2 gene, which produces only 5% to 10% SMN protein; the more SMN2 copies, the higher SMN protein production. Accordingly, the number of SMN2 copies inversely correlates with the severity of the SMA phenotype and explains the spectrum of disease severity, from the lethal neonatal-onset (SMA1), to early childhood- (SMA2), adolescent- (SMA3), and adult-onset (SMA4).
Two new revolutionary therapies for SMA now bring some hope for this devastating and untreatable disease. The first drug, approved in 2017, is nusinersen, an antisense oligonucleotide. Because SMN2 is subject to aberrant pre–messenger RNA splicing with variable skipping of exon 7, which leads up to 10% production of normal SMN protein, modulation of pre-mRNA splicing of the SMN2 gene, as nusinersen does, promotes SMN protein. On this basis, nusinersen could be an effective therapy. In phase II, open-label studies, nusinersen prolonged survival of SMA infants and improved motor function of some children with SMA2 and SMA3, leading to provisional FDA approval. The drug was now tested in the first controlled, phase III efficacy study, which convincingly demonstrated a greater motor milestone response in 41% of infants compared with 0% of the controls, with the likelihood of overall survival higher in the nusinersen group (HR, 0.37; P = .004).1 Infants with a shorter disease duration at screening were more likely to benefit and be alive from nusinersen than those with a longer disease duration.1 The authors concluded that early treatment should maximize the benefit of the drug. Nusinersen, given with intrathecal injections, is the first drug helping infants whose only destiny is death. Although the study is remarkable, there are concerns. As pointed out in the accompanying editorial,2 the follow-up observation period was rather short, and it is very likely that lifelong repetitive intrathecal treatments will be required; whether these therapies will continue being effective in improving or stabilizing the disease for many years remains unclear. The cost is astronomical, reaching $750,000 the first year and $375,000 for every year after that, generating a number of justifiable ethical dilemmas that have not yet been resolved.
The second study investigated the use of gene therapy involving a single intravenous administration of nonreplicating adeno-associated viral serotype 9 vector (scAAV9) that contained the normal human SMN1 sequence.3 Although the primary outcome was safety and the study was open-labeled and limited to only 15 infants, all patients after one intravenous administration were alive and event-free at 20 months of age, compared with an 8% survival rate of historical cohorts. Of 12 patients who received a high gene therapy dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently.3 Even if the study is preliminary, the results were striking in demonstrating longer survival and superior achievement of motor milestones. Whether the expression of the scAAV9 gene is sustained or declines over time, remains unknown; this is important as the same treatment may not be repeated because antibodies against AAV capsid proteins are anticipated to be formed,2 and there will be a need for concurrently applied immunosuppressive therapies, which may not be effective or safe. In spite of these serious limitations, the possibility that gene therapy can show such a remarkable effect is exciting. As suggested,2 the combination with nusinersen may prove a useful scheme in SMA; starting first and early with gene therapy and continuing thereafter with nusinersen for long-term maintenance.
What became clear from these studies, and of great importance to clinicians, is that early treatment in pre-symptomatic SMA patients is a viable strategy to save lives. Notwithstanding the extraordinary cost of these therapies, diminishing long-term disability and saving lives in heretofore untreatable or lethal SMA subtypes offers a remarkable glimpse of hope for this devastating spectrum of hereditary motor neuron diseases.
Click on any of these tags to subscribe to Topic Alerts. Once subscribed, you can get a single, daily email any time PracticeUpdate publishes content on the topics that interest you.
Visit your Preferences and Settings section to Manage All Topic Alerts
Additional Info
- Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732.
- van der Ploeg AT. The dilemma of two innovative therapies for spinal muscular atrophy. N Engl J Med. 2017;377(18):1786-1787.
- Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713-1722.
Disclosure statements are available on the authors' profiles: