Combination Therapy Improves Quality-of-Life in Spinal Muscular Atrophy

An investigational drug used in conjunction with nusinersen (Spinraza) boosted the efficacy of the newly-approved drug in mice with spinal muscular atrophy (SMA).

Nusinersen was approved by the FDA in December 2016, and became the first drug approved for the treatment of SMA.

In a study published in Neuron, investigators boosted nusinersen therapy, which resulted in improvements in survival time, body weight, and motor movements in mice with SMA.

Investigators sought to identify mechanisms that could affect the levels of survival motor neuron (SMN) proteins in neurons. For the study, they scanned the genomic database UCSC Genome Browser, and identified 2 genetic sequences that matched the opposite DNA strand of the SMN gene.

The investigators used programs that analyzed the DNA sequences, and found that they were made up of 1 long RNA. However, the type of RNA differed from traditional genes, in that it did not make up or code for the instructions of a protein, but rather was noncoding.

The long noncoding RNA (Inc-RNA) was detected in human embryonic kidney cells, brain cell samples, and neurons derived from the stem cells of healthy individuals, as well as those with SMA type 1 and 2.

In healthy individuals and mice, there were high levels of SMN protein before birth, which then decreased after birth. The opposite pattern was observed with the SMN Inc-RNA, which was at low levels in human spinal cord samples before birth, and increased after birth. The findings were also confirmed in embryonic mice.

The investigators also sought to increase SMA gene product levels, the messenger RNAs (mRNAs), and the protein levels, by silencing or removing the SMN Inc-RNA, according to the study. The investigators created 8 different bits of DNA that matched the antisense version of the SMN Inc-RNA, which would bind to, and break down, the Inc-RNA.

HeLA cells and neurons from embryonic mice with different amounts of antisense DNA were incubated. The results of the study showed that the more DNA bits added, the more mRNA levels increased that code for SMA protein. The most effective DNA bits were ASO-A and ASO-B.

The findings suggest that the SMN Inc-RNA appears to decrease the levels of the SMN mRNA, thus, preventing more SMN protein from being made, according to the authors.

To determine whether shutting down the SMN Inc-RNA would increase SMN levels, and slow or stop SMA, the investigators injected 400 milligrams per kilogram of ASO-A DNA bits at day 1 and day 3 after birth into newborn mice with severe SMA. At day 10, there was a 70% reduction of SMN Inc-RNA in the brains of the treated mice. However, survival, body weight, and the ability to get on their feet did not improve compared with mice injected with saline.

Since nusinersen cannot cure the disease, the investigators sought to determine if ASO-A in conjunction with nusinersen would further improve muscle form and function in mice with SMA, according to the study.

The mice were injected with either ASO-A alone, 50 milligrams per kilogram of nusinersen alone, both ASO-A and nusinersen, or saline at day 1 after birth. A total of 15 mice received each treatment.

The results of the study showed that the combination therapy increased the average survival to 37 days, with 4 of the mice living more than 120 days.

Mice who received saline and ASO-A, lived an average of 18 days, while mice treated with nusinersen monotherapy, lived an average of 25 days. Additionally, mice who received the combination therapy reached an average body weight of 14 grams after 50 days. Mice with nusinersen monotherapy did not gain weight past 6 grams. Healthy mice weighed about 20 grams after 50 days.

The investigators also examined the number of times the mice reared up their hind legs within a minute of being put in a clear cylinder. Healthy mice reared approximately 6 times, mice with SMA treated with the combination therapy reared approximately 4 times, and mice treated with either drug alone reared about 2 times.

“We don’t know yet if the SMN Inc-RNA actually plays a role in the disease, but it is a convenient target that we’ve used to our advantage to treat spinal muscular atrophy in mice,” said investigator Charlotte Sumner, MD. “We still want to determine how the Inc-RNA does its job and when it does it[s] job, and that will give us a better handle on how to target it more effectively.”

The investigators cautioned that the booster therapy will not come to market, or even be available for use in human clinical trials, anytime soon. It must first undergo years of animal testing for safety and efficacy.

If the findings are confirmed in additional studies, the treatment could significantly improve the quality of life in patients with SMA, according to the authors. As for now, the results offer at least 1 path to extend the efficacy of nusinersen.