Renewed Hope: Novel Treatments for Spinal Muscular Atrophy Improving Outcomes
Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease that presents as progressive muscle weakness secondary to loss of lower motor neurons in the brainstem and spinal cord. With an incidence of 1 in 10,000 live births, SMA is the most common genetic cause of death in infancy, but new treatments may soon change this poor prognosis. SMA occurs when a child possesses two pathogenic mutations in the SMN1 (survival motor neuron 1) gene necessary for survival of motor neurons in the brainstem and spinal cord responsible for control of the body's muscles. The severity of the disease can be modified by the number of survival motor neuron 2 (SMN2) gene copies, which serve as a backup. The more copies of SMN2 an individual has, the milder the symptoms of SMA they may demonstrate.
Clinically, children with SMA manifest features including muscle weakness and atrophy, low muscle tone, lack of reflexes, and tongue fasciculations. SMA is divided into 4 subtypes depending on the severity of symptoms and age of onset. Type 1 is the most common and severe, accounting for ~60% of new diagnoses, with symptom onset prior to 6 months of age. Children with SMA Type 1 have poor head control, a weak cry, poor oral motor skills with inability to speak and difficulty feeding, and inability to sit independently or progress in gross motor milestones such as crawling, standing or walking. Over time, they develop respiratory weakness leading to respiratory failure. Without therapeutic intervention, only 8% of children with SMA Type 1 survive to 20 months of age. Children with Type 2 SMA typically become symptomatic between 6-18 months of age and have life expectancy into adolescence. While they may learn to sit independently, most do not gain the ability to stand or walk independently. Type 3 SMA begins after 18 months of age. While children initially acquire the ability to walk independently, as the disease progresses they may lose this skill. Type 4 SMA is the mildest form presenting with progressive weakness in adulthood, though patients typically maintain their ability to walk. People with Type 3 and 4 SMA have normal life expectancies.
While the prognosis for SMA, particularly Type 1 and 2, has been poor, new treatments promise the potential to alter long term outcome of this devastating disease. Unlike most medications which aim to treat the symptoms of disease, these new therapies are aimed at the genetic basis of the disease.
In December 2016, the first FDA-approved drug for the treatment of SMA was released. Nusinersen (i.e Spinraza™) is an anti-sense oligonucleotide working at the RNA ( ribonucleic acid) level. This drug acts on the splice site of the SMN2 gene product converting it to a normally functioning protein similar to that made by the SMN1 gene. The treatment is administered intrathecally (i.e via spinal tap) and must be given six times over the first year and three times per year thereafter. Initial trials of nusinersen included only children with SMA type 1, although the FDA approved the treatment for all types of SMA. Fifty percent of the children treated with nusinersen showed a motor milestone response compared to none of those receiving placebo. Of these motor achievements, 8% were able to sit independently and 1% were able to stand – outcomes previously unheard of for this type of SMA. There were also improvements in requirements for respiratory support and survival with the use of nusinersen.
In May 2019, a second drug was approved by the FDA to treat SMA. Zolgensma, works via gene therapy to replace one copy of the mutated SMN1 gene with a normal functioning copy via a viral vector. Unlike nusinersen, this treatment is a one-time intravenous infusion given over one hour. The drug is currently approved for children with SMA of any type up until the age of 2 years. Children enrolled in the initial trial's high dose cohort showed remarkable improvements – 92% of them gaining head control, oral feeding, speaking, and sitting independently. Seventeen percent were walking independently – again a remarkable improvement in outcome for this disease. There was no decline in respiratory status and for a small percentage of patients there was improvement in ventilatory status/needs. Unfortunately, not all insurance companies have adopted policies to cover this drug which may limit availability of this new treatment option.
While the treatment approach of these two therapies is different, one thing is clear, there are now options available to patients diagnosed with SMA that modify the disease leading to more favorable outcomes, regardless of age or type. Data in all cases show that the earlier treatment is provided, the better the ultimate outcome. In 2018, SMA was recommended as an addition to the newborn screening panel, however, this must be implemented on a state-by-state basis. Fortunately, there are several companies that offer free genetic testing to detect the disease early. If you are suspicious that your patient has SMA, early diagnosis is key to survival. Please do not hesitate to contact the Neuromuscular team at Cook Children's for an expedited evaluation of a hypotonic infant if there is high suspicion for spinal muscular atrophy.