In infants with type-1 spinal muscular atrophy (SMA), one dose of onasemnogene abeparvovec gene-replacement therapy seems safe and improves motor and respiratory capabilities, according to five-year results of an ongoing follow-up study. "Gene therapy, if given early to treat SMA type 1 - a severe inherited, lethal disease - will significantly help the baby," said lead researcher Dr. Jerry R. Mendell of Nationwide Children's Hospital in Columbus, Ohio. "Most infants will have prolonged survival and improved function or have minimal symptoms. This treatment reverses the outcome, and babies can be treated like their healthy siblings. We believe that this therapy may represent a cure for many with this devastating disease." "This was the first systemically delivered form of gene therapy to be approved by the U.S. Food and Drug Administration (FDA)," Dr. Mendell told Reuters Health by email. "It was also the first gene therapy using peripheral limb infusion of the gene with this much success." In the five-year update of the 15-year observational, follow-up START study, Dr. Mendell and colleagues analyzed data from 13 of the original participants at one academic pediatric hospital. As reported in JAMA Neurology, the children ranged in age from around 2 to 4 years at the beginning of the follow-up study. All participants had symptomatic type-1 SMA and two copies of the survival motor neuron 2 (SMN2) gene. The children had previously been treated with intravenous onasemnogene abeparvovec: either one low dose (6.7 x 10^13 vector genomes per kilogram of body weight (vg/kg)), or one therapeutic dose (1.1 x 10^14 vg/kg). The median time since dosing among all participants was 5.2 years: 5.9 years in the three low-dose patients, and 4.8 years in the 10 therapeutic-dose patients. Prior to baseline, four participants in the therapeutic-dose group had needed noninvasive ventilatory support. At follow-up, all 10 children in the therapeutic-dose group remained alive and none needed permanent ventilation. They also maintained their motor milestones, and two of them reached the new milestone of standing with assistance, without the use of nusinersen. Serious adverse events occurred in eight babies, including acute respiratory failure, pneumonia, dehydration, respiratory distress, and bronchiolitis. There were no deaths. "Onasemnogene abeparvovec transfers a gene targeting the cause of SMA, the deadliest single-gene disease of infancy," explained Dr. Ann C. Modrcin, director of the Division of Rehabilitation at Children's Mercy Kansas City, in Missouri. "This study is needed to monitor the medication's safety and effectiveness." "Long-term serious adverse events or gene-therapy-related events can have serious consequences, including liver compromise, malignancy, or new neurologic or autoimmune disorders," she added. "That none of these adverse effects were noted during the study period is reassuring for parents and clinicians who are wary of gene-based treatments." "It is crucial to note that the babies with the best motor and respiratory outcomes were treated early while there were either no symptoms or few symptoms of the disease," said Dr. Modrcin, who was not involved in the study. "This mirrors our own center's experience treating 15 babies with SMA." "Early treatment requires early diagnosis, which is only possible through widespread newborn screening for SMA," she said. "As of May 1, 2021, 36 states include SMA in their newborn screening panels, meaning 74% of babies will be diagnosed at birth rather than months later, after symptoms have emerged." Dr. Modrcin advises that, although gene-replacement therapy is expensive, states and insurance providers should consider that early treatment avoids much higher future costs and enables children with SMA live fuller lives with normal activities, including sports and careers. Novartis Gene Therapies, Inc. supported the study. Dr. Mendell and several co-authors report financial ties to the company. Dr. Modrcin stated that she has no conflicts of interest. —Lorraine Janeczko Source
