Scientists investigate new strategy to treat spinal muscular atrophy in infants

May 8, 2018, The Scripps Research Institute

Spinal muscular atrophy (SMA) is a genetic disease that can leave infants with weak muscles and trouble breathing. Many with the disease die before age two. To help these patients, doctors need therapies that target the genetic mutation and stop its progression.

Now, scientists at the California Institute for Biomedical Research (Calibr) and The Scripps Research Institute have discovered how a potential new targets SMA. The research, published recently in the journal Proceedings of the National Academy of Sciences, could guide the development of other drugs for genetic diseases.

"In fact, if we can learn more about the drugs in the pipeline for genetic diseases, we can learn more about the diseases themselves," says Kristen Johnson, PhD, a principal investigator at Calibr and co-lead author of the study.

Until recently, patients diagnosed with SMA had no treatment options. The recent approval of a drug called nusinersen, marketed as Spinraza, has given families hope, and now scientists are working to design therapies that could be even more effective.

One potential drug is RG-7916, a small molecule currently in phase 2 clinical trials run by pharmaceutical company Roche (which no had involvement in this study). In the study, Johnson and her colleagues examined molecules similar to RG-7916 to better understand how the drug works.

"Understanding the mechanisms behind drugs is so critical for treating the right kinds of patients," Johnson says. "Plus, the more you understand about the mechanism of a drug, the better physicians can watch out for possible side effects."

The researchers suspected that to really be effective, RG-7916 would need to target a process called RNA mis-splicing. In addition to causing SMA, RNA mis-splicing is responsible for a family of devastating genetic illnesses, from Hutchinson-Gilford progeria syndrome, which causes premature aging, to Menkes disease, which causes severe neurological impairment and often kills patients before age three.

In these diseases, something has gone wrong in the way the cell reads the genome to produce proteins. During this process, threads of genetic information, called preRNA, need to be spliced into useful fragments. In SMA, molecules called splicing silencers mistakenly swoop in, blocking splicing and stopping the production of the protein, called survival of motor neuron (SMN).

Working closely with study co-leader Peter Schultz, PhD, president of Scripps Research, Johnson and study first author Jingxin Wang, PhD, discovered that analogs to RG-7916 indeed targeted the SMN2 pre-RNA sequence that causes SMA. With the drug molecule in place, the pre-RNA sequence became more flexible and is spliced correctly and ultimately leads to the full length SMN protein.

"This drug basically allows the equipment that drives splicing—which we call splicing enhancers—to sit on the preRNA in right location," says Johnson. "This causes the right fragmenting of the RNA so it produces the right protein."

RG-7916 also binds to a nearby protein, and this combined pre-RNA and protein binding interaction makes the drug very specific for targeting the SMA mutation.

Roche has also published data showing that RG-7916 is targeting the pre-RNA splicing process. Johnson says the complementary studies are an encouraging sign that RG-7916 is on the right track, although it will still need to pass key toxicology studies and clinical studies. In the meantime, Johnson is excited to see if drugs to target RNA mis-splicing can be designed to help many more patients.

"For example, there are less severe forms of SMA that affect older kids and teenagers, but researchers have primarily tested therapies in infants," says Johnson. "We could use what we've learned how to try to treat other forms of the disease."

There are only a handful of RNA-targeting drug candidates right now, Johnson says. By studying these drug candidates, scientists may be able to better guide the design of future pharmaceuticals and find more clues to what works and doesn't work.

"Now that we have more understanding of this class of drugs, could we build a small library of molecules to start tackling some of these other diseases," says Johnson.

Explore further: Therapeutic RNA corrects splicing defect that causes familial dysautonomia

More information: Jingxin Wang et al, Mechanistic studies of a small-molecule modulator of SMN2 splicing, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1800260115

Related Stories

Therapeutic RNA corrects splicing defect that causes familial dysautonomia

April 30, 2018
Scientists at Cold Spring Harbor Laboratory (CSHL) have identified a therapeutic RNA molecule that corrects the error in genetic processing that leads to familial dysautonomia, a rare inherited neurodegenerative disorder. ...

New method identifies splicing biomarkers for liver cancer

March 2, 2018
Because liver cancer is particularly diverse, genetically, and prone to relapse, identifying biomarkers that can predict disease progression is a critical goal in the fight against it.

Preliminary study suggests drug may help babies with spinal muscular atrophy

April 18, 2018
A preliminary study suggests that an investigational drug may help increase protein levels in babies with spinal muscular atrophy. The open-label study is released today and will be presented at the American Academy of Neurology's ...

Better understanding amyotrophic lateral sclerosis by looking at how cells change

March 19, 2018
It took eight long years of research, but now an international team led by neuroscientists at Université de Montréal has discovered a basic molecular mechanism that better helps understand how Lou Gehrig's disease, or amyotrophic ...

Orally delivered compounds selectively modify RNA splicing, prevent deficits in SMA models

August 7, 2014
Today the journal Science published results of a preclinical study demonstrating that treatment with orally available RNA splicing modifiers of the SMN2 gene starting early after birth is preventing deficits in a mouse model ...

Genes may cause tumor aggressiveness and drug resistance in African-American prostate cancer

June 30, 2017
A form of genetic variation, called differential RNA splicing, may have a role in tumor aggressiveness and drug resistance in African American men with prostate cancer. Researchers at the George Washington University (GW) ...

Recommended for you

3-D printed biomaterials for bone tissue engineering

August 13, 2018
When skeletal defects are unable to heal on their own, bone tissue engineering (BTE), a developing field in orthopedics can combine materials science, tissue engineering and regenerative medicine to facilitate bone repair. ...

Artificial intelligence platform screens for acute neurological illnesses

August 13, 2018
An artificial intelligence platform designed to identify a broad range of acute neurological illnesses, such as stroke, hemorrhage, and hydrocephalus, was shown to identify disease in CT scans in 1.2 seconds, faster than ...

Researchers create specialized delivery methods to help treat cancer, other disorders

August 13, 2018
More than 100 years ago, German Nobel laureate Paul Ehrlich popularized the "magic bullet" concept—a method that clinicians might one day use to target invading microbes without harming other parts of the body. Although ...

Scientists identify why some kidney transplants don't work

August 13, 2018
Scientists have discovered a 'molecular signature' for the allostatic load – or 'wear and tear' of kidneys – which could help clinicians understand why some kidney transplants don't work as well as expected.

Tiny fruit flies unravelling the secrets to end of life

August 10, 2018
We are used to seeing them dive-bombing our glass of wine or hovering around the fruit bowl.

Scientists find that common dietary elements cure lethal infections, eliminating the need for antibiotics

August 9, 2018
Antibiotic use is driving an epidemic of antibiotic resistance, as more susceptible bacteria are killed but more resilient strains live on and multiply with abandon. But if antibiotics aren't the end-all solution for infectious ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.