Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease that may be affected before the child is born. The most severe cases, if left untreated, usually pass away before the age of 3. Recently, scientists from St. Jude Children's Research Hospital in the United States published a unique study in the renowned medical journal New England Journal of Medicine. This article introduces the world's first case of using oral medication risdiplam to treat SMA patients in the mother's uterus before birth. After more than two years of birth, this child has not observed any identifiable symptoms of SMA. The researchers stated that this study demonstrates the feasibility of prenatal treatment for SMA and supports further research on this method.
Risdiplam is a small molecule SMA therapy jointly developed by Genentech, a subsidiary of Roche, and PTC Therapeutics. It is a small molecule mRNA splicing regulator targeting the SMN2 gene. Although the SMN2 gene can also express SMN protein, due to mRNA splicing errors, the normal expression level of SMN protein is very low, which cannot compensate for the SMN protein loss caused by SMN1 gene mutations. Evrysdi improves the expression of normal SMN protein mRNA levels by regulating the splicing of SMN2 gene mRNA, thereby alleviating symptoms in SMA patients. It was first approved by the FDA in 2020 (trade name Evrysdi) for the treatment of spinal muscular atrophy in infants and adults aged 2 months and above.
In this study, the parents of the affected children were known carriers of the SMN1 gene mutation, and a baby with SMA-1 disease was born before the current treatment was available and passed away at 16 months. In this study, genetic testing conducted through amniocentesis confirmed that the infant will have SMA-1 after birth. Previous preclinical studies have shown that risdiplam related drugs can be delivered through the placenta. Therefore, after obtaining approval from the FDA and local review agencies, researchers administered risdiplam (5 milligrams per day) to pregnant women during the last six weeks of pregnancy.
Shortly after birth, the baby was diagnosed with three developmental abnormalities: ventricular septal defect (which has disappeared on its own), underdeveloped optic nerve, and asymmetrical brainstem, resulting in delayed vision and overall development. These abnormalities are believed to occur during the early stages of fetal development, prior to exposure to risdiplam. In preclinical studies, no developmental abnormalities were observed using risdiplam before or after birth in animals.
This baby continued to take risdiplam after birth and received treatment with Zolgensma (onasemnogene abeparvovac), an SMA gene therapy developed by Novartis, at almost two years old. She underwent regular check ups at St. Jude and is now two and a half years old. Throughout the entire evaluation period, no symptoms related to SMA were found, including muscle hypotonia, weakness, loss of reflexes, or muscle bundle tremors.
In the past decade, significant breakthroughs have been made in the field of SMA diseases. The US FDA has approved three innovative therapies for SMA, including the antisense oligonucleotide therapy Spinraza (nusinersen) developed by Ionis, as well as the gene therapy Zolgensma and oral therapy Evrysdi mentioned earlier. Evrysdi's oral tablet formulation has recently received FDA approval, providing patients with more flexibility in medication. However, currently approved drugs are used after the birth of infants, and for some severe SMA patients, they already show symptoms of the disease at birth. Dr. Finkel stated in an interview with Nature that there is still room for improvement in the treatment of these patients. We look forward to the results of this study leading to more new treatment strategies and further improving the lives of patients.
<Reprinted from WuXi AppTec>
