"Beyond anyone’s most optimistic expectations.” That’s what you want to hear from a scientist when years of basic research form the basis of a clinical trial, one that is declared a winner before the trial is even finished.

Adrian Krainer, a molecular geneticist at the Cold Spring Harbor Laboratory (CSHL), found a way to manipulate a key protein linked to the deadly childhood disease spinal muscular atrophy (SMA). Until now, the disease had no treatment; more than 90 percent of infants born with SMA died before turning two.

In December the journal Lancet published results of a Phase II study of the drug nusinersen, marketed as Spinraza. The trial ended early: Treatment slowed progression of the disease, improved survival, and in some cases demonstrated major improvement in muscle function. The FDA approved the drug on December 23.

It’s very good news in the SMA world. “With nusinersen, these infants are not only living longer, but they’re living better,” said Richard S. Finkel, MD, lead author of the Lancet study and chief of neurology at Nemours Children's Hospital in Orlando. “SMA is no longer a death sentence. This treatment is by no means a cure, but it is more than we've ever been able to offer these families before.”

Said Krainer, “News of the approval is incredibly gratifying. Most gratifying to me is the thought that thousands of families will now be able to see their loved ones benefit from the drug’s therapeutic effects.”

The pathway to approval for Spinraza makes for a compelling investigative story, which we can start about 40 years ago when Richard Roberts of CSHL and Phillip Sharp, then of MIT, first described RNA splicing. There’s no time or space to explore the wonderful intricacy of RNA biology, but keep this basic idea in mind: DNA, the blueprint, makes RNA, the messenger, which in turn makes protein, the structural component needed in the body. RNA regulates when a protein gets made, and how much. Roberts and Sharp shared the 1993 Nobel Prize for this work.

Krainer came into the picture in 1999. He saw a presentation at an NIH workshop by researchers who described a genetic coding problem with SMA. Two genes code for survival of motor neuron protein, the primary building block for the production of motor neurons. In kids with SMA, one of these gnes contains a mutation in the RNA. Krainer, by now well schooled in RNA splicing, took up the challenge of modifying the bad gene to allow more normal production of motor neurons.

Krainer’s team found the splicing error in the faulty gene. They fixed it using molecules of modified RNA called antisense oligonucleotides. When delivered to cells, these molecules bind to an exact location on the RNA associated with the target gene, which has the effect of editing the RNA message. Krainer enlisted the Carlsbad, CA based biotech Ionis to develop the gene editing drug. In 2012, Ionis in turn licensed development of the drug, now known as nusinersen, to Biogen, the leading maker of multiple sclerosis medicines.

It’s a story for another day, but get ready for pharma sticker shock: nusinersen will carry a price tag of $750,000 for the first year of treatment, with annual treatments of about $375,000 per year per patient.

Note: a few days ago Johns Hopkins researchers identified a drug that acts as a “booster” in conjunction with nusinersen. In work published in Neuron, the researchers report that the combination therapy improved survival time, body weight and motor movements in mice. The booster won’t be on the market yet anytime soon, pending many tests and approvals.

OK, so SMA is a terrible disease, but it’s very rare. Do oligonucleotides have any relevance to other conditions? Yes, there are dozens of clinical trials ongoing to test oligonucleotide gene-expression modification. There are trials ongoing for several forms of cancer, hepatitis, colitis, diabetes, asthma and others.

Last September FDA gave conditional approval to eteplirsen, a treatment that may help about 17 percent of people with Duchenne muscular dystrophy. This drug (which must still get FDA sign-off for a complete a clinical trial) modifies a mutation of the gene for dystrophin, allowing more robust production of this key protein. (This was a controversial FDA decision, made against the vote of an advisory committee. Muscular dystrophy advocates helped tilt the decision).

What about spinal cord injury? It’s not a genetic disease but certainly there are codes that could be modified to optimize recovery. I have not heard of anything clinical yet but the research is certainly happening. The Michael Selzer lab at Drexel, for example, just published work that used an oligonucleotide technique to block the effect of a molecule called RhoA in lampreys; this enhanced axon regeneration and reduced cell death after SCI.

Phil Horner, scientific director for The Houston Methodist Neurological Institute’s Center for Neuroregenerative Medicine (and former Associate in the Reeve Foundation International Research Consortium on Spinal Cord Injury) published a paper last fall called “Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System.” He discusses ways to improve delivery of genetic therapies, including the use of oligonucleotides.

I asked Phil to freely speculate a little regarding the use of antisense genetic modification in the spinal cord injury model:

The ability to modify protein assembly through antisense is very exciting. I can think of a few applications for SCI. One is the immune system. I wonder if you couldn't use antisense to modify translation of splice variants that would tip the balance between pro-inflammation and the resolution of inflammation.

I also think there may be many potential application for the regeneration side. For example, it may be possible to influence the expression of channel subunits thast are represented in immature neurons. Subunits of NMDA receptors can influence whether channel activation leads to plasticity instead of excitotoxicty.

I also imagine you could potentially modify protein localization in either glia or neurons that would change the way the extracellular matrix or signaling molecules would function. For example, modification of the localization of regeneration-associated protein could be used to improve regenerative signaling, or in the case of cytoskeletal modifiers, promote the position of the factors toward the dendrites to promote neuronal growth.

I think there are many opportunities, once you have a tool that you can direct to a specific population of neurons or glia to change either the expression of a splice or the active form of a protein that may be naturally blocked due to inflammation or other degenerative phenomenon. You can pick many pathways that might be interesting to test.