"Hey look, standing with one leg!" cries Emma Larson.

Scientific American March 2020 pp46-53. Antisense Therapy “Finally Making Sense” “A long-disdained therapy that target RNA is achieving spectacular success” by Lydia Denworth.

Most of us today have a basic understanding of cellular and molecular biology. Especially that DNA encodes mankind’s general and our specific design blueprint. Chromosomes carrying DNA are carried from generation to generation from father and mother. During development and throughout life, for many cellular processes, DNA is transcribed to several forms of RNA and most importantly mRNA or messenger RNA. mRNAs carry the transcribed DNA instructions that are specifically translated into amino acid building blocks to make completely functional structural and active proteins like enzymes.

As a simple analogy, a form of disease happens when you move your arm and hand to shift gears, say into reverse, but that action is not translated to movement because the transmission fails. In the case of spinal muscular atrophy, or SMA, neurological signals for movement fail-converting the thought to move has a transmission failure-so the wheels don't move. The result is devastating. Emma Larson “loved the bouncer…and she "crawled with gusto". Then at 13 months, Emma’s legs stopped working” laments her mother.

Researchers investigated Emma's genomic DNA and discovered she lacked the SMN1 gene. The SMN1 gene contains the instructions for making a critical protein called SMN or survival motor neuron. Without SMN, motor nerves fail to function, shrink (atrophy) and die. Emma did have the SMN2 gene that normally encodes only a non-functional protein. Researchers, in this narrow field of research, had discovered that the SMA2 gene actually could be salvaged to make a functional SMN. They designed a form of RNA that would bind to the SMN2 gene RNA receptor with a hand and glove fit. Early studies using Anti-Sense RNA in cell culture were not successful but later animal and human studies were.

An anti-sense RNA called Nusinersen and now marketed as Spinraza was produced for use in humans. “Nusinersen, injected into spinal fluid….homes in on the RNA strands produced by SMN2…” binding a critical region such that SMN instructions remain in place and functional SMN is made.

Although some of Emma’s nerve function was lost early in infancy “she was able to crawl”…”within months of receiving Spinraza" Infants born with SMA can now be treated. “Twenty five newborns with the most severe SMA mutation were given the drug at birth. They are four years old now-and developing normally”. Over 8,400 patients are now being treated.

This remarkable story of translating basic science into a molecular therapy is one of vision, belief and persaverance by investigators. Since the 1990s, they tackled one failure mechanism after the other. This successful group increased the anti-sense drug affinity for its target by modifying a part of the RNA backbone and made other changes to the drug that “improved safety and tolerability”.

Now that successful methods have been identified to turn-off or turn-on genes using anti-sense or related therapies, researchers are seeing success with other rare diseases and there’s hope and some evidence for early success with other neurodegenerative diseases including Huntington’s Disease. Read the article for more scientific information and Emma’s story.

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