480. Gene Therapy for Spinal Muscular Atrophy Type 1 Shows Potential to Improve Survival and Motor Functional Outcomes
Authors: Jerry R. Mendell, Samiah Al-Zaidy, Richard Shell, W Dave Arnold, Louise Rodino-Klapac, John T. Kissel, Thomas W. Prior, Carlos Miranda, Linda Lowes, Lindsay Alfano, Katherine Berry, Christopher Petek, Kathleen Church, Lyndsey Braun, Sarah Corcoran, Kathrin Meyer, Shibi Likhite, Arthur HM Burghes, Kevin D. Foust, Brian K. Kaspar
Journal: Molecular Therapy (2016)

Spinal muscular atrophy (SMA) is the most common genetic cause of infant death with mutations of survival motor neuron 1 gene (SMN1) on chromosome 5q13 affecting 1 in 10,000 live births. SMA manifests as symmetrical weakness of proximal extremity, axial, intercostal and bulbar muscles. Longitudinal studies in SMA type I with 2 SMN2 copies show progressive weakness with a need for continuous non-invasive ventilation or death by a median age of 10.5 months. The mean rate of change over time in CHOP INTEND (CI) score is -1.27 points/year for all SMA type I infants. In this ongoing gene therapy trial, the criteria for enrollment for the first 10 patients was as follows: onset of symptoms before 6 months (m), homozygous loss of the SMN1 gene, 2 copies of SMN2, and no c. 859G>C exon 7 mutation. Two cohorts (Table 1) received intravenous AVXS-101(scAAV9.CB.SMN), Group 1 (n=3) 6.7×1013 vg/kg and Group 2 (n=7) 2.0×1014 vg/kg. The secondary endpoint for this safety study is death or need for >16 hours/day of noninvasive ventilation for at least 2 weeks. The minimal therapeutic dose cohort-1 had a mean age of 6.3±0.75m and a CI of 16.33±10.50 at baseline. Currently, this cohort is age 23.6±1.95mo with a CI of 22.3±13.65. The therapeutic dose cohort-2 was stratified by age at gene transfer. Group 2A (Pts 6 and 10) were treated at the earliest time points in the study 1.9m and 0.9 m, respectively with CI of 47 and 50 at baseline. Currently, this group is age 12.2m and 5.8m; and has a normal CI of 64. Group 2B (Pts 4, 5, 7, 9) had a mean age of 4.6±0.86m with a CI of 29.25±3.69 at baseline. Currently, this group is age 14.5±3.44m with a CI of 52±2.45. And Group 2C (Pt 8) was 7.9m with a CI of 12 at baseline. Currently, this patient is age 15.4m with a CI of 11. Electrophysiology studies showed increased compound motor action potentials (CMAPs) matching early treatment. It appears that an older age at enrollment (i.e. Pt 8 at 7.9m) with low CI results in stabilization with the therapeutic dose. Tabled 1Gene delivery DoseGroups based on Age at GTAge* (m) at GT means ± SDCurrent Age* (m) mean ± SDCl Score at GT mean ± SDCurrent Cl Score mean ± SD6.7 × 1013 vg/kgGroup 1Pts 1,2,3 6.3 ± 0.75m23.6 ± 1.9 m16.33 ± 10.5022.3 ± 13.652.0 × 1014 vg/kgGroup 2APts 6,10 1.9m, 0.9m12.2m, 5.8m47, 5064, 64Group 2BPts 4,5,7,9 4.6 ± 0.86m14.5 ± 3.44m29.25 ± 3.6952 ± 2.45Group 2CPt 8 7.9m15.4m1211 Open table in a new tab Treatment-related serious adverse events in this trial were limited to transient liver enzyme elevation without clinical manifestations and correlated with high level IFN-γ ELISpot assays to AAV9 capsid. This transaminasemia responded well to short-term prednisolone treatment. In summary, gene therapy for SMA type 1 appears to be neuroprotective allowing motor development to continue. At a higher CI score of 47- 50 with an enrollment age of 1-2 months, group 2A normalized to a score of 64. At a mid-level CI score with enrollment at age 4.6±0.86 m, improvement for group 2B appears to be equivalent to the SMA Type 2 phenotype. This trial provides evidence that gene therapy may provide patient benefit when compared to natural history. For example, natural history would predict that CI would decrease by 1.27 points per year and mortality of 75% of SMA Type 1 patients at 13.6 months, whereas 6 of 10 patients receiving gene therapy have passed the 13.6 month milestone. These results support the need for further studies of this promising therapeutic approach.