Nusinersen against spinal muscular atrophy

A cure for a genetic disease

Maxim Rousseau, Polit.<url>, based on the materials of Science: Novel drug rescues babies with fatal neurodegenerative disease

The new drug helps cells bypass a genetic defect that causes a severe congenital disease – spinal muscular atrophy. This disease destroys the motor neurons of the spinal cord and brain, depriving the patient of the ability to move. In the most severe cases, children with spinal muscular atrophy die before the age of two from respiratory muscle paralysis. Children with moderate forms of the disease live longer and may even live to adulthood, but they also have serious motor disorders.

Different variants of mutations leading to spinal muscular atrophy occur with a frequency from one in 8000 to one in 12,000 newborns. Approximately one in 50 adults turns out to be a carrier of a mutated variant of the gene, but since this variant is recessive, the symptoms of the disease do not manifest. If both parents have the mutation, the chance of having a sick child is one in four. The mutation is localized in the SMN-1 gene, it leads to the death of motor neurons. In mild cases of the disease, the SMN-2 gene encoding the same neuron helps to preserve some of the neurons. The number of copies of this gene depends on how much the symptoms of muscular atrophy will manifest. For a complete solution to the problem of SMN-2 activity, as a rule, it is not enough.

In 2003, Adrian Krainer and Luca Caregni from the Cold Spring Harbor Laboratory designed synthetic RNA-like molecules that change the process of translation of the SMN-2 gene into matrix RNA and further synthesis of the corresponding protein based on it. As a result, they were able to significantly increase the production of this protein by cells, which in patients with spinal muscular atrophy should have compensated for the breakdown of the SMN-1 gene. They reported on the results achieved in the journal Nature Structural Biology. Their work was noticed by neuroscientist Fran Bennett from the pharmaceutical company Ionis Pharmaceuticals. He contacted Krainer and Karenyi and offered to develop a cure for spinal muscular atrophy based on the molecule they created. As a result, a drug was created, which is a fragment of modified RNA (antisense oligonucleotide), which participates in transcription and ensures the creation of a full-length protein chain based on the SMN-2 gene. The medicine was named nusinersen.

Chemical structure of nusinersen. Fig.: Drugspider

After a long period of preclinical development and testing, clinical trials of nusinersen were launched in 2011. In the second phase of these trials, it prolonged the life and improved respiratory function in children with severe forms of spinal muscular atrophy compared with data from the medical histories of children who did not receive such a drug. Nusinersen was given to children who had symptoms of the disease at the age of three weeks to six months. The drug was injected into the cerebrospinal fluid.

Of the 20 children who participated in the trials in 2014 and 2015, 13 remained alive and are able to breathe independently, whereas usually half of children with this form of the disease die or end up on artificial ventilation at the age of one year. Only four children died in the experimental group. Two aged 5 and 11 months died from respiratory tract infection, two aged 7 and 12 months – from respiratory failure. However, when examining the brain and spinal cord cells of these children, it turned out that in them, too, nusinersen acted on the SMN-2 gene, forcing it to produce a complete protein molecule. The number of copies of the corresponding matrix RNA in their cells was from two to six times higher than is usually the case in children who died from this disease.

In August 2016, the third phase of drug trials began. It was performed on infants with the most severe type of spinal muscular atrophy (known as SMA-1, or Werding-Hoffman disease). It manifests itself in the first six months of life, children do not hold their heads, are unable to sit on their own, have difficulty breathing, sucking and swallowing. The trials were soon interrupted, as doctors considered it unethical to deprive children from the control group of access to the drug, the effectiveness of which had already become obvious. Ionis Pharmaceuticals and Biogen have given the drug the trade name SPINRAZA and have applied for its approval by the U.S. Food and Drug Administration and the European Medicines Agency.

The drug was also tested on patients with another form of the disease (SMA-2, or Dubovitz disease). It is typical for children aged six months to one and a half years. Patients can sit and eat on their own, but are not able to walk. Children from two to twelve years old participated in the tests. In November of this year, the trial was stopped for the same reasons as the previous one, and doctors gave the medicine to all the children involved.

Stanley Crooke, CEO of Ionis Pharmaceuticals, says that children with severe forms of muscular atrophy remain alive, and, according to the impression of doctors, the longer the treatment is carried out, the more the condition of children improves. The company expects that the use of the drug in the United States will be officially allowed in the first quarter of 2017.

The results of the tests are described in an article published by The Lancet (Finkel et al., Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study – VM).

Portal "Eternal youth" http://vechnayamolodost.ru  08.12.2016