▎WuXiEdited by Kant Content Team

Spinal Muscular Atrophy (SMA) is a progressive neurodegenerative disease that may affect patients before birth. The most severely affected children usually pass away before the age of 3 if left untreated. Recently, scientists from St. Jude Children's Research Hospital published a unique study in the prestigious New England Journal of Medicine, introducingThe world's first case of treating an SMA patient before birth using the oral drug risdiplam in the mother's uterus.This pediatric patient has not shown any recognizable signs of SMA more than two years after birth.The researchers stated that these findings demonstrate the feasibility of prenatal SMA treatment and support further research into this method.

Risdiplam is a small-molecule SMA therapy jointly developed by Genentech, a subsidiary of Roche, and PTC Therapeutics.It is a targetedSMN2Small Molecule mRNA Splicing Modulators of Genes。SMN2Although genes can also express SMN protein, the incorrect mRNA splicing results in very low levels of normal SMN protein expression, which cannot compensate.SMN1SMN protein deficiency caused by gene mutation.Evrysdi modulates throughSMN2Splicing of gene mRNA to increase the level of mRNA capable of expressing normal SMN protein, thereby alleviating symptoms in SMA patients.It was first obtained in 2020.FDA Approval(Evrysdi), used to treat spinal muscular atrophy in infants aged 2 months and above, as well as adult patients.

In this study, the parents of the pediatric patients were bothSMN1Known carriers of genetic mutations who previously had an infant with SMA Type 1 disease that passed away at 16 months. In this study, genetic testing via amniocentesis confirmed that the infant would be born with SMA Type 1. Preclinical studies had already shown that risdiplam-related drugs can cross the placenta. Therefore, after obtaining approval from the FDA and local regulatory authorities, researchers administered risdiplam (5 mg daily) to the pregnant woman during the last six weeks of pregnancy.

Shortly after birth, the infant was diagnosed with three developmental abnormalities: ventricular septal defect of the heart (which resolved on its own), hypoplasia of the optic nerve, and asymmetry of the brainstem, resulting in delayed vision and overall development. These abnormalities were considered to have occurred during the early stages of fetal development, prior to exposure to risdiplam. In preclinical studies, these developmental anomalies were not observed when risdiplam was administered to animals either before or after birth.

The infant continued to take risdiplam after birth and received Zolgensma (onasemnogene abeparvovec), the SMA gene therapy developed by Novartis, just before turning two. She undergoes regular check-ups at St. Jude and is now two and a half years old.No symptoms related to SMA were observed throughout the assessment period, including hypotonia, weakness, loss of reflexes, or fasciculations.

"Our primary goal was to evaluate feasibility, safety, and tolerability, so we are very pleased to see that both the parents and the children are doing well," said Dr. Richard Finkel, the corresponding author of the study and director of the Center for Experimental Neurotherapeutics at St. Jude. He added that this study demonstrates the safety and feasibility of treating infants in utero before birth, providing support for larger, more comprehensive studies.

The field of SMA has seen continuous major breakthroughs over the past decade.The U.S. FDA has approved three innovative therapies for SMA, including byAntisense oligonucleotide therapy developed by IonisSpinraza（nusinersen）, as well as the aforementioned gene therapyZolgensmaAnd oral therapyEvrysdiEvrysdi'sOral Tablet FormRecently, it also received FDA approval, providing more flexibility for patient medication. However, currently approved drugs are used after the baby's birth, and for some severe SMA patients, symptoms of the disease are already evident at birth. Dr. Finkel told Nature in an interview that there is still room for improvement in the treatment of these patients. We look forward to this research result spawning more new treatment strategies to further improve the lives of patients.

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