By Elena Moro
For January 2018, we have selected: Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. NEJM 2017;377:1713-1722.
Spinal muscular atrophy (SMA) is caused by loss or dysfunction of the gene encoding survival motor neuron 1 protein (SMN1). Disease severity is also influenced by a second gene, SMN2, which can produce smaller amounts of this protein. The most severe form is SMA type 1, a devastating disease presenting in babies with a median age of death or ventilator dependence of 11 months. At the age of 20 months, only 8% of children with SMA1 survive without permanent ventilator support. The goal of this study was to evaluate gene therapy as a potential treatment for SMA type 1. Complementary DNA encoding the missing SMN protein was delivered intravenously using a viral vector (adeno-associated viral serotype 9 (scAAV9)). In preclinical trials, this approach had been shown to induce SMN expression in motor neurons and peripheral tissues and significantly improved survival in mouse models.
In this prospective study, 15 patients with genetically confirmed SMA1 (homozygous SMN1 exon 7 deletion, and two copies of SMN2) were enrolled in two cohorts according to the dose of administered gene therapy. On patient was excluded due to the presence of antibodies to the viral vector. The first cohort (three patients, mean age 6.3 months) was enrolled from May 2014 to September 2014, and received a single intravenous low dose (6.7×1013 vg per kilogram of body weight) of scAAV9. The second cohort (12 patients, mean age 3.4 months) was enrolled from December 2014 to December 2015, and received a higher dose (2.0x 1014 vg per kilogram). An elevation of liver enzymes occurred in the first patient, so all subsequent patients also received oral prednisolone (1 mg/kg daily) for one month.
The primary outcome was the safety of gene-replacement therapy. Secondary outcomes were the time until death or permanent ventilator assistance, achievements in motor milestones (e.g. sitting unassisted) and improvement in motor scores over 3 months using the CHOP INTEND (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale.
The procedure appeared safe. Thirteen patients experienced adverse events such as an elevation in serum aminotransferase levels or an infection but, up until August 2017, all 15 patients studied had reached the age of 20 months or more without the need permanent mechanical ventilation. All patients had increased CHOP INTEND scores at 3 months. Patients with the higher dose treatment had a mean increase of 24.6 points from a mean baseline of 28.2 points, 11/12 could sit unassisted for several seconds and achieved the ability to speak; two patients could walk independently. Benefits were maintained approaching two years of follow-up.
In the context of such an aggressive disorder, these results are startling. A single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN was able to significantly improve motor function and survival in children with SMA1 for the first time. Notably, benefit was maintained at the last available follow-up. The treatment appears safe so far and treatment-related increases in aminotransferase levels were effectively managed with oral prednisolone. Limitations of the study include the lack of a contemporaneous control group and the small sample size. Further studies are needed to evaluate the effectiveness and safety of this approach in the long-term, but these results are extremely promising, represent a landmark in the field of gene therapies and appear highly relevant to patients and their families. Of note, in the same issue of NEJM, another, larger sham-controlled trial (Finkel et al) looking at the effect of four intrathecal infusions of nusinersen, an antisense oligonucleotide which modifies splicing of the SMN2 gene to promote increased production of full-length SMN protein, also showed striking positive results.
Dr Tom Jenkins, senior clinical lecturer and consultant neurologist, Sheffield Institute for Translational Neuroscience, UK