Writing assignment #4: Summary for a Primary Article

John Paul Cross

Genetics, Dr. Rinehart-Kim

Spinal Muscular Atrophy, or SMA, is a rare monogenic disease that is caused by improper coding in the first survival motor neuron (SMN1), and results in infants with extremely poor coordination, inability to support themselves, steady constant decline in respiratory and esophageal function necessitating use of an external breathing apparatus, and in many cases, death. Most studies before this one had mainly focused on increasing the role SMN2 played in covering for the lack of SMN1 by injecting nusinersen into the child in hopes of improving SMN2 expression. The researchers proposed that if a copy of SMN was delivered via a viral vector complex (scAAV9), that the gene could be successfully spliced into the patient’s genes.

The study chosen focused on finding a remedy for Spinal Muscular Atrophy (SMA) by injecting infants suffering from SMA with viral vectors containing the missing genes responsible for preventing SMA. The study was conducted from May 2014 through December 2015 in two distinct cohorts, with cohort 1 receiving a weaker dose, and cohort 2 receiving a stronger one. DNA was applied intravenously to 15 patients in several saline doses. Patients were then judged by a set of criteria commonly used by the WHO to determine motor function in infants, including unassisted sitting and the CHOP INTEND scale.

By the end of the study’s legally permissible window, all patients had surpassed the 20-month milestone without the need for ventilation, compared to the usual mark of only 8% of patients afflicted with the disease making it that far without ventilation. Patients also displayed markedly increased CHOP INTEND scores when compared to historical results, with the patients from the second cohort averaged 24.6 points higher scores than historical results. In addition, patients from the second cohort displayed varying milestone progress, with two being able to stand and walk independently. In contrast, all historical cases had been incapable of meeting even the lowest milestone of sitting unattended for five seconds, a feat that 11 out of the 12 in the second cohort had achieved. 11 of the 12 were also able to swallow independently from the last recorded follow up, with 4 being able to consume matter orally. Averse side effects were limited, with enzyme imbalances being treatable with prednisolone.

In summary, the injection of SMN-laden viral vectors lead to drastically increased quality of life and motor control in patients from both cohorts. All patients injected with the viral vector carrying SMN had significantly longer lifespans, eclipsing the 20-month milestone which only 8% of historical cases had previously achieved. The second cohort showcased historically unobserved milestones and drastically increased motor control, suggesting that the treatment was highly effective at limiting and in some cases reversing the effects of SMA1.

Citation

Mendell, J. R. et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine 377, 1713-1722 (2017).