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AANEM News Express

Science News: Two Reports on Spinal Muscular Atrophy Treatments - Nusinersen and Gene Replacement Therapy

Submitted by David R. Mayans, MD, News Science Editorial Board
Edited by Lisa M. Williams, MD, News Science Editorial Board
Finkel, R, et al. Nusinersen vs Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377:1723-32.
This study was a double-blind, sham controlled phase 3 trial of Nusinersen with primary endpoints of motor milestone response and event free survival. Nusinersen is an antisense oligonucleotide drug that modifies pre-mRNA splicing of SMN2 to promote increased production of SMN protein. This medication is given in a series of intrathecal injections. Initially, 80 patients were randomized to the Nusinersen group and 41 controls with follow-up up to 394 days. The average age at first dose was 163 days (5 months). In an interim analysis, the motor milestone response was 41% to 0% in the control group so the trial was terminated early. The final analysis included all 121 infants. 51% of patients in the Nusinersen group had motor-milestone response, 22% had head control, 8% could sit, and 1% could stand. None in the control group reached any of these milestones. At the time of final analysis, 39% in the Nusinersen group had died or gone on permanent assisted ventilation compared to 68% of the control group. An increase in the CHOP INTEND scale was seen in 73% of patients on Nusinersen compared to 3% in control. 36% of patients in the Nusinersen group had an increase in peroneal and ulnar CMAP compared to 5% in the control group. In subgroup analysis, patients who received this at a younger age had better outcomes than those at a later age. 
Comment: This is an important study that helps validate a previous phase 2 trial of Nusinersen for use in spinal muscular atrophy type 1. This medication not only prevents motor decline but also has improvements in motor milestones which has not been seen before in SMA. The treatment appears to be safe and is more effective if started early in the disease. It would be interesting to see a combination of therapy of Nusinersen and adeno-associated virus serotype 9 gene replacement therapy for the combined effect.

Submitted by David R. Mayans, MD, News Science Editorial Board
Edited by Nandita S. Keole, MD, News Science Editorial Board
Mendell, J, et al. (2017). Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine. 377. 1713-1722. 10.1056/NEJMoa1706198.
Spinal muscular atrophy (SMA) type 1 is a devastating illness of the motor neurons presenting in early childhood. Symptoms are usually present at 1 month of age, and by 20 months of age, only 8% survived without ventilatory support. In this study, 15 children with genetically confirm SMA1 (homozygous SMN1 exon 7 deletions and two copies of SMN2) were selected for administration of an adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. The Mean age was 6.3 yrs (5.9-7.2). Patients were enrolled in 2 cohorts: 3 at a low dose, and 12 at a high dose. The AAVS9 was delivered in a one-time dose intravenously. The primary outcome was safety of the infusion. The initial cohort of 3 was given the low dose which was tolerated well, so the dose was increased for the second cohort which was recruited at a later time. Secondary outcomes included time until death, need for permanent ventilatory support, and motor milestone achievements using the CHOP INTEND (Children’s Hospital of Philadelphia Infant test of NM disorders) scores. The mean age of treatment was 6.3 months in the first cohort and 3.4 months in the second cohort. The first patient had elevated ALT and AST, so the protocol was changed to allow for Prednisolone around the time of administration which attenuated elevations in other patients. 2 other patients required extra prednisolone due to elevations of liver enzymes. All patients had reached 20 months of age and none required permanent ventilatory support. Patients in both cohorts had significant increases in CHOP INTEND scores (7.7 in cohort 1 and 24.6 in cohort 2) with most being able to maintain a score more than 40. 9 of 12 patients in cohort 2 could sit unassisted for 30 seconds. 11 of 12 achieved head control. 2 were able to crawl, pull to stand, and walk independently. 11 of 12 had the ability to speak.
Comment: This is another groundbreaking study in the treatment of SMA with a targeted gene therapy used to replace the nonfunctional SMN gene. This treatment not only prevented the motor decline in the patients, but actually allowed them to have motor improvements and reach milestones not seen in this disease previously. It will be interesting in the future to see how this method may work in patients at an even younger age or if this could be used in combination with Nusinersen. 

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