The Tartan

Amniocentesis confirmed the fetus lacked both copies of the SMN1 gene, leading to an SMA diagnosis, and the presence of two copies of the SMN2 gene was a predictive sign of SMA type 1.

Proteins play a vital role in our bodies, contributing to transport, structural integrity, enzymatic functions, and protection, to name a few. Genes — segments of deoxyribonucleic acid (DNA) — possess the information necessary to construct proteins. They are composed of exons, which code for proteins, and introns, which do not.

Protein synthesis begins with transcription in which the enzyme ribonucleic acid (RNA) polymerase binds to a specific region of the gene’s DNA sequence, and reads off the DNA to transcribe the precursor messenger RNA (pre-mRNA), which is composed of introns and exons.

Shortly after, the pre-mRNA’s non-coding regions (introns) are removed and coding regions (exons) are joined together in a process known as splicing, which converts pre-mRNA into mature mRNA.

The mature mRNA then exits the nucleus and enters the cytoplasm, where it attaches to the ribosome — made of ribosomal RNA (rRNA) and proteins — to undergo translation. Transfer RNA (tRNA) molecules carry amino acids, the building blocks of proteins, to the mRNA. The tRNA then brings the necessary amino acids to the mRNA in the ribosome, where the amino acids are linked together to form a protein.

Spinal muscular atrophy is a group of hereditary disorders that affect the production of the survival motor neuron (SMN) protein. The SMN protein helps maintain the health and normal functioning of motor neurons, specialized nerve cells in the brain and spinal cord that help control movement in the arms, legs, face, tongue, chest, throat, and skeletal muscles, which support posture, maintain body temperature, and store nutrients, among other things. The disorder is a leading cause of infant mortality.

The SMN protein is primarily produced by the SMN1 gene. We inherit one copy of the SMN1 gene from each parent — one on each chromosome. SMA is an autosomal recessive disorder, meaning two mutated SMN1 genes must be expressed for the disorder to exist. If you inherit one healthy and one mutated SMN1 gene, you are a carrier of the disorder. In 94 percent of all SMA cases, the mutation is a deletion in the exon 7 segment of the SMN1 gene.

There are five types of SMA: type 0, I, II, III, and IV, with types II-IV being less severe than the others. The different types of SMA are in part attributed to the number of copies of the SMN2 gene, which neighbors the SMN1 gene and can produce SMN proteins, though to a lesser extent.

Unlike the SMN1 gene, individuals can possess more than two copies of the SMN2 gene due to gene duplication events in the formation of the egg and sperm or during the process of genetic recombination. Thus, more than one copy can be inherited from each parent. There is a single nucleotide difference between SMN1 and SMN2, a difference that disrupts splicing in exon 7 of SMN2. Consequently, the SMN proteins produced by SMN2 are less stable. Although the SMN proteins produced by the SMN2 gene are not always fully functional, an increased number of copies of the SMN2 gene is associated with less severe forms of SMA.

Of the types of SMA, type I — also known as Werding-Hoffman disease — is the most common form of SMA and is the one the fetus was diagnosed with. Type I is often diagnosed before 6 months of age with symptoms including severe muscle weakness, as well as difficulty breathing, coughing, and swallowing. Children suffering from type I often do not live past age two.

The U.S. Food and Drug Administration has approved three drugs to help treat SMA in newborn infants, one of which is risdiplam (brand name Evrysdi), a drug manufactured by the biotech company Roche. Risdiplam works by directly interacting with the messenger RNA constructed by the SMN2 gene thus, increasing the amount of SMN protein being produced. Risdiplam is unique in that it can be administered orally, making it the first and only treatment for SMA that can be taken at home.

Until now, risdiplam has only been administered to newborn infants. Having lost their previous child at 16 months of age as a result of the disorder, the parents sought to begin treatment prenatally. They found it at St. Jude Children’s Research Hospital under the direction of Dr. Richard S. Finkle, director of the Center for Experimental Neurotherapeutics and a member of the Department of Pediatric Medicine at St. Jude.

At first glance, this seems unethical. Risdiplam has never been tested prenatally on humans, though it has on rats and rabbits. In rats, high doses of risdiplam administered during pregnancy caused developmental toxicity in the fetus but no birth defects occured. Maternal toxicity in the mother, which included weight loss and general health deterioration, also occurred with high doses of risdiplam. Similar outcomes resulted when risdiplam was administered to pregnant rabbits. In fact, risdiplam was advised against being used during pregnancy due to some studies suggesting a risk of fetal harm and others suggesting adverse effects on reproductive organs.

However, the FDA and local institutional review board at St. Jude approved the use of risdiplam for the expecting mother, allowing for the single case study. Both parents consulted with an unaffiliated advocate and provided written and informed consent. Roche provided scientific advice on the safety of prenatal administration and supplied the parents with risdiplam free of charge for the study under a confidentiality agreement with St. Jude Children’s Research Hospital. And besides, the clinical trial was the parents’ idea.

Between 32 weeks of gestation and delivery at 38 weeks, the mother orally ingested a 5 mg dose of risdiplam daily and was monitored weekly. Amniotic fluid testing at birth suggested the drug was reaching the fetus. There was a 33 percent concentration of risdiplam in the amniotic fluid and a 69 percent concentration of risdiplam in the cord blood. The infant shows no symptomatology or signs of developing SMA, which is believed to be the result of prenatal administration of risdiplam. 

The infant, however, was born with other developmental disorders: ventricular septal defect (a.k.a. a heart murmur, which resolved), optic nerve hypoplasia, and brainstem asymmetry. Experts considered these developmental disorders to have occurred in early fetal development prior to risdiplam being administered prenatally.

The child, now two and a half years old, has continued to take risdiplam orally every day and shows no manifestation of SMA. The child will likely need to consume risdiplam for the remainder of her life and is recommended lifelong monitoring by Finkle.

Finkle does not believe this single clinical investigation should be generalized, but rather that it supports the idea of prenatal administration of risdiplam for fetuses diagnosed prenatally.