Persistence and Rescue: The Birth of China's First Approved RNA Therapy

Article source: Medical Rubik's Cube Pro

Author: Li Yuan

On February 28, 2019, the National Medical Products Administration (NMPA) formally approved the marketing of Nosinassan Sodium (active ingredient: Nosinasana)
.

Spinal muscular atrophy is an autosomal recessive genetic disease, also known as progressive muscular atrophy
.

Due to the lack of awareness of premarital examinations and pregnancy examinations among the population or the limitations of detection technology, most children only know that they have the disease after they develop symptoms
.

In China, Noxinagen sodium is the first drug approved for the treatment of spinal muscular atrophy.
Although it is expensive, it brings hope to parents who are waiting in the dark
.

"At least my child is saved
.

The birth of Nocinnat is actually a story that promotes a defective gene to save another mutant gene
.

In patients with spinal muscular atrophy, the mutation of SMN1 reduces the expression of SMN protein, the motor neurons in the spinal cord and brainstem degenerate, and the muscles gradually become weak and atrophy
.

SMN2 is the "brother" of SMN1.
Although SMN2 is almost identical to SMN1 and encodes the same SMN protein, it is a defective gene.
Most of the precursor mRNA of SMN2 will be abnormally spliced ​​and translated into short and unstable The peptide does not produce stable and sufficient SMN protein
.

The team of Dr.
Adrian Krainer of Cold Spring Harbor Laboratory has been studying a splicing activator SRSF1 since the 1980s.
They found that when the RNA information of SMN2 is spliced, the expression of SRSF1 is lost, which causes exon 7 to be skipped.
, The lack of key information makes SMN2 unable to express the normal amount of SMN protein
.

Source: ThermoFisher

The key to the defect has been found, and the next step is to fix this defect
.

In 2004, Dr.
Krainer’s team and Ionis researchers began to collaborate to design drugs to correct the skipping of exon 7.
Sub 7 is included to form a full-length SMN2 transcript, which will produce a full-length functional SMN protein after translation
.

Source: Nature

Since then, this ASO drug has been continuously optimized and its efficacy has been proven
.

In December 2016, only 3 months after the submission of the New Drug Application (NDA), the US Food and Drug Administration (FDA) approved the marketing of Nosinassan (trade name: Spinraza), and Nossinasana became the world's number one.
A drug for the treatment of myelogenous muscular atrophy
.

Since then, Nosinathan has been approved by the European Medicines Agency (EMA), the Japanese Medicines and Medical Devices Agency (PMDA) and NMPA.
Now patients with spinal muscular atrophy in more than 50 countries and regions around the world can use this drug Get treatment
.

Note: The generic name of nusinersen listed in China is nusinersen and nusinersen abroad

Reference materials:

[1] The world's first spinal muscular atrophy treatment drug Noxinassen Sodium Injection was officially launched in China (Source: PR Newswire)

[2] Killer Disease, Miracle Drug (Source: Cold Spring Harbor Laboratory)

[3] Hua, Y.
, Sahashi, K.
, Rigo, F.
, et al.
Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model.
Nature (2011)

[4] Milestones in antisense RNA research (Source: Nature)

[5] Roberts, TC, Langer, R.
& Wood, MJA Advances in oligonucleotide drug delivery.
Nat Rev Drug Discov (2020)