May was a big month in the world of gene therapy. The FDA approved Zolgensma (onasemnogene abeparvovec-xioi) on May 24th for the treatment of children less than two years of age with spinal muscular atrophy (SMA). This was a tremendous step forward in the care of children born with this devastating genetic condition, but it comes with a daunting price tag of $2.1 million for the injection required to administer the purported one-time treatment.

The excitement over this treatment milestone has been tempered recently by the FDA’s announcement of an investigation into data manipulation impacting the accuracy of product testing data – information the manufacturer allegedly held until after FDA approval was granted. While the FDA states that it remains confident in Zolgensma’s safety and efficacy, advances in treatment should not come at the cost of ignoring research ethics.

Early success and hope

SMA is the most common genetic cause of death in infancy/childhood, historically devastating parents’ hopes and dreams for their child’s future. SMA refers to a group of inherited neuromuscular disorders characterized by progressive muscle weakness affecting the skeletal muscles that control so many activities of daily living – literally moving and breathing. SMA is subdivided into five clinical groups based on age of onset and clinical course: type 0 through type IV (most severe to least severe). SMA is the second most common lethal, autosomal recessive disease in Caucasians, after cystic fibrosis.

With the approval of Zolgensma, as well as Spinraza (nusinersen) in 2016, families now have treatment options for the first time. In clinical trials for Zolgensma to date, many enrolled children have experienced remarkable outcomes – the majority have been able to sit independently with full head control. And, most remarkably, two of 12 (17%) have demonstrated major motor milestones, including crawling or walking independently. Compared to the severe, often lethal, disabilities seen in untreated children with SMA, there is cause for celebration with these early results.

A careful look at treatment population and results

While celebrating this medical milestone and potential victory for the families and individuals impacted by this condition, some caution should be preserved until additional data is available. It is premature to generalize these results to all patients with SMA. The impressive results reported to date have only been seen in a very select group of patients with SMA: Those who are missing both functional copies of the SMN1 gene but have two typically functioning copies of the SMN2 gene. The number of SMN2 copies present is important because it currently is the best predictor of whether a child will be more severely affected (zero SMN2 copies) or more mildly affected (four or more SMN2 copies) by their disease. The data available in the medical literature does not address whether the same beneficial outcomes will be seen in all patients with SMA (those with different copy numbers of SMN2). Without further research, one cannot assume that Zolgensma will have the same benefit in all patients with SMA.

Some children with SMA will not be eligible for treatment with Zolgesma. They may be too symptomatic, carry too few (e.g., zero) or too many (e.g., four) copies of SMN2, or be diagnosed too late. This may be very difficult for families to understand, thus it is important to realize that the FDA approval is currently based on limited data from a select population. Right now, it isn’t known if this treatment works in those most severely affected (children with zero copies of SMN2), nor do we know if the benefits outweigh the risks in those who may not have any problems until adulthood (those with four copies of SMN2). It is sobering to note, while remarkable results have been demonstrated for many, two children have died in the clinical trials to date. As our understanding of this treatment grows and these questions are answered, the population eligible for treatment will evolve.

Long-term data is often lacking with new FDA approval process

What is the lifetime impact of treatment? No long-term outcome data for Zolgensma is yet available. A similar type of gene therapy used to treat hemophilia A, valoctocogene roxaparvovec, suggests a guarded view on gene therapy. Recently reported data indicates that the treatment impact declined over time. It appeared the treatment was stable for at least three years, but was not able to provide a full cure for affected individuals. Ethically, one must contemplate how best to define “cure.” Early data in children treated with Zolgensma suggest this treatment can significantly mitigate symptoms of SMA, as some were able to achieve impressive outcomes, but the results were variable and it did not achieve resolution of symptoms in all. Without longer term data available, the question regarding variability and durability of the response to Zolgensma also still remains unanswered.

While this new era in SMA treatment brings hope to families with the availability of two different treatment options, it also creates a critical point to address: Which treatment option is best for each patient? With two FDA-approved therapeutics to treat individuals with SMA which have very different mechanisms of action, administration, and cost, families and providers may have a hard time making decisions. The current attempts to address comparative effectiveness of the treatment options have been hampered by slight but important differences in sub-populations treated and highlights the dire need for additional research.

Overall, the impact of Zolgensma in treating children with SMA cannot be understated with its potential to alter the natural history of this devastating condition. However, heralding this treatment as a cure needs to be tempered by the very limited data published to date, the complex genetics of this condition, and the variability in treatment outcomes. Attention to and understanding of the risk/benefit ratio will be paramount when considering treatment options. Ethically, we must also demand nothing less than honesty and transparency in the reporting of data in the interest of the care and safety of patients. 


Cure SMA: A non-profit dedicated to dedicated to the treatment and cure of spinal muscular atrophy (SMA), funding groundbreaking research and providing families the support they need for today.

National Institute of Neurological Disorders and Stroke: A part of the National Institutes of Health.

SMA News Today: A science and health publishing website designed to help educate patients on clinical trials that may be of interest to them and to help patients contact the centers conducting the research.

InformedDNA provides proven expertise in applying genetics to clinical trials, clinical research programs and natural history studies. To learn more, just submit the short form below; email us at; or, give us a call at 800-975-4819.


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