Plant in Chinese Medicine Seen to Raise SMN Protein Levels in Mouse Model of SMA

A plant used in traditional Chinese medicine boosts the production of functional survival motor neuron (SMN) protein — whose lack underlies the development of spinal muscular atrophy (SMA) — and ameliorates disease symptoms, a study in a mouse model finds.

The results, “Improvement of Spinal Muscular Atrophy via Correction of the SMN2 Splicing Defect by Brucea javanica (L.) Merr. Extract and Bruceine D,” were published in Phytomedicine.

SMA comprises a group of neurodegenerative disorders characterized by the gradual loss of motor neurons — the nerve cells responsible for controlling voluntary muscles — in the spinal cord, leading to muscle weakness. It is caused by mutations in the SMN1 gene, which provides instructions for making the SMN protein that is essential for motor neuron survival.

People have a gene similar to SMN1, called SMN2, that can also produce the SMN protein. SMN2 is usually healthy in SMA patients and is known to influence disease course, depending on the number of copies present.

But unlike SMN1, SMN2 tends to produce shorter, unstable versions of the SMN protein that lack exon 7 through a process called alternative splicing. (An exon is the coding sequence of a gene that provides instructions to make proteins; alternative splicing is the process of creating different proteins from the same gene.)

Ways of correcting the splicing defects associated with SMN2 to boost the production of a fully functional SMN protein is one of the approaches being studied to treat SMA, and one treatment based on this approach exists.

Spinraza (nusinersen), by Biogen, is an approved disease-modifying treatment for SMA that acts as a splicing corrector.

But, as this study’s researchers wrote, due to Spinraza’s “invasive route of administration [spine injection], extremely high cost, and a few side effects, more practical and effective drugs are desperately needed.”

The Korean scientists investigated whether natural plant compounds could be used to correct the splicing defect of SMN2 in a mouse model of SMA.

They first scanned the literature, looking for plants used in traditional medicine in the context of SMA. Their search yielded 492 plant extracts thought to contained certain compounds of benefit.

To understand which have compounds of relevance to the splicing defect of SMN2, investigators treated cells that had been genetically-modified to produce a gene reporter with each of these extracts. The screening was based on a SMN2 gene reporter containing luciferase — a light-emitting enzyme from fireflies — that would only emit light when SMN2 was spliced correctly.

This work spotted 12 plant extracts that seemed to correct SMN2 splicing. Researchers then performed quantitative real-time polymerase chain reaction (qRT-PCR) — a technique used to measure the expression levels of genes — in SMA patient-derived fibroblasts, looking for extracts that could restore the production of full-length SMN messenger RNA (mRNA).

Of note, RNA is the molecule that serves as the template for the production of proteins; gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.

Three extracts noticeably increased full-length SMN mRNA production. After further tests, researchers decided to focus on the extract that increased SMN protein production by 30%.

This extract belonged to Brucea javanica, a shrub used in traditional Chinese medicine to treat several diseases, including malaria and cancer.

Mice with severe SMA-like symptoms were then treated with both B. javanica extract and its major active ingredient, Bruceine D. Results showed that both treatments significantly improved the animal’s muscle function and prolonged their lifespan.

“Our work revealed that B. javanica and Bruceine D correct the SMN2 splicing defect and improve the symptoms of SMA in mice. These resources will provide another possibility for development of a plant-derived SMA drug candidate,” the investigators concluded.