Until a few years ago, patients with spinal muscular atrophy could only take part in clinical trials of new drugs, use physical therapy and treatments that improve the quality of life - and wait for someone to finally develop an effective therapy. They have lived to see it: recently the development of SMA can be stopped, because a drug is available that slows down the course of the disease and gives many patients hope for independence.

There is an effective cure for SMA, scientists recently announced. However, the history of treating spinal muscular atrophy is not long - an effective cure for the disease has been sought for years.

SMA is one of the rare diseases that can appear already in infants, but it cannot be detected in any ultrasound examinations that are ordered to expectant mothers during pregnancy. It manifests itself in its acute form in the first weeks or months of life.

Parents notice that the baby, who has been developing harmoniously so far, suddenly begins to tire easily, sucks and breathes with difficulty, cries very quietly, or actually squeals, because he has no strength for anything else. The disease also develops in older children, as well as in adolescents and adults (and the later the first symptoms appear, the milder it is usually).

Patients with spinal muscular atrophy gradually lose the ability to control their own body as their muscles become weaker and weaker. Most of them are confined to a wheelchair after some time and need help in every, even the simplest, activity.

All these symptoms are caused by a deficiency in the production of the SMN protein (responsible for the proper functioning of motor neurons), which occurs as a result of an error in the SMN1 gene located on the 5th chromosome. When there is not enough of this protein, neurons die and muscles begin to atrophy, leading to partial or even complete paralysis.

In Poland, one in 35 people has a mutation in the gene responsible for coding the SMN protein. If both parents have it, the risk of a child having SMA is 25 percent. It is estimated that every year in our country 40 babies are born with spinal muscular atrophy.

Comfort of life for SMA patients

Symptoms of spinal muscular atrophy have been known for centuries, and the first official description of the disease known to medicine dates back to 1891 - thenAustrian neurologist Guido Werdnig described her infant form. Since a similar description was written almost simultaneously by another neurologist, the German Johann Hoffmann, this form of SMA is also referred to as the Werdnig-Hoffmann syndrome.

For many years there was no effective treatment. In order to provide patients with comfort of life, and in some forms of the disease, also to extend the time when they are relatively independent, symptomatic treatment was implemented: physical therapy, orthopedic treatment, and respiratory support. As long as the patient was walking, the aim of the therapy was to prolong this state as long as possible, improving - through daily, individual rehabilitation - muscle strength, respiratory efficiency - and preventing joint contractures.

Much depended, however, on the patient's condition and the degree to which he was disabled. In the case of people whose disease was completely immobilized, efforts were made to prevent the development of scoliosis, contractures and respiratory failure.

Difficulties in treating SMA

The genetic basis of SMA was described in 2005, and since then, work on drugs that could reverse the SMN protein deficiency has been in full swing. Several substances have been tried to treat spinal muscular atrophy, both those intended to repair a "faulty" gene and those that would increase the amount of the SMN protein.

Experimented with chemicals that increased the activity of the SMN2 gene (a twin gene SMN1, which also produces the SMN protein, but in insufficient amounts) - growth hormone, prolactin, drugs used to treat cancer or drugs from the class of histone deacetylase inhibitors are only some of them.

Researchers also looked at natural polyphenols (curcumin, resveratol), aminoglycosides, and substances that helped in similar cases in animals - sodium butyrate and sodium phenylbutyrate. A moment ago it was found that some patients are helped by valproic acid combined with l-carnitine: unfortunately, it turned out that in most cases this substance also has no effect.

There was also some hope for TRH to prevent neuronal death, and a substance that has been used successfully to treat amyotrophic lateral sclerosis - these too have proved to be sterile, as have induced stem cells.

New perspectives in the treatment of SMA

Nearly 120 years after the disease was first described, a light appeared in the tunnel: scientists began to wonder if it was possible to modify the assembly of the SMN2 gene in such a way that it would encode more of the SMN protein. During the research, it was observed that a number of such properties havesubstances, including aminoglycosides and antibiotics from the tetracycline group.

In 2008 it turned out that the SMN2 gene can be modified with synthetic oligonucleotides. Five years later, clinical trials of the first drug substance containing synthetic nucleotides began, which aroused high hopes of experts.

Soon, other molecules were also investigated: branaplam (increasing the level of the SMN protein by modifying the assembly of the pre-mRNA of the SMN2 gene, RG7800 (which modified the assembly of the SMN2 gene in such a way that significant amounts of the missing SMN protein were formed) and a substance called risdiplam , which significantly increased the amount of SMN protein in all tissues.

Currently, branaplam is still in the research phase, while the results of the research on risdiplam are so promising that the manufacturer of this substance has applied for approval in the USA for the treatment of all forms of SMA. However, there are two molecules in the clinical trial phase that work to strengthen the muscles of patients with SMA: reldesemtiv and SRK-015.

Success in treating SMA

December 23, 2016 is a breakthrough date in the treatment of SMA: on this day, the manufacturer of the drug based on synthetic nucleotides received approval from the American Food and Drug Administration (FDA) to introduce this substance to treat all forms of this disease in the US and countries which directly comply with FDA decisions.

On December 30, 2022, a similar decision was issued by the European Commission, allowing the drug to treat all forms of SMA in EU countries. The first Polish patient was included in the drug program on February 27, 2022. Currently, as emphasized by prof. dr hab. n. med. Maria Mazurkiewicz-Bełdzińska, head of the Department of Developmental Neurology at the Medical University of Gdańsk, the treatment covers all Polish patients with SMA, regardless of their age and type of disease.

What do we know about this drug? It's an oligonucleotide, a synthetic DNA fragment. The molecule of this substance is so large that it does not cross the blood-brain barrier, so the drug must be administered directly to the cerebrospinal fluid surrounding the spinal cord - only this way of application allows it to reach the motor neurons that are part of the spinal cord cord.

After administration, it penetrates the cell nucleus of motor neurons and modifies the assembly of the SMN2 gene in such a way that it begins to encode more than before the SMN protein, "taking over" the function of the SMN1 gene. The therapy, combined with daily rehabilitation, slows down the progression of the disease and improves he alth in many patients. But not all of them: as Prof. dr hab. n.med. Maria Mazurkiewicz-Bełdzińska, the drug is not able to restore the efficiency of those people whose nervous system is damaged due to the progression of SMA and who are not able to move their muscles on their own.

However, administration of the drug when the patient is still relatively fit, and therefore at the beginning of the disease, allows to modulate the damaged gene to such an extent as to prevent further degenerative changes.

By giving the drug to infants before the first symptoms appear, you can also prevent the development of the most severe form of the disease - SMA01. This was confirmed by the NURTURE study conducted since 2015, which included newborns with genetically proven spinal muscular atrophy who had not yet developed symptoms of the disease - each of the 25 children in early treatment can sit without support, and 22 of them are able to walk independently. .

Most of these children acquired these skills at the same time as he althy children. Therefore, both doctors and parents of children with SMA are now postulating that all newborns undergo screening for SMA, thanks to which sick children could receive the drug as early as the first week of life.

Gene therapy for SMA

Since May 2022, a drug substance for gene therapy in children up to 2 years of age is also available in the USA. This substance contains viruses from the scAAV9 family - after administration, they penetrate the cells of motor neurons, transmitting to the nucleus a synthetic DNA sequence corresponding to the SMN1 gene. The encoding of the missing SMN protein begins almost immediately, and its level increases significantly over the next few days - which is why this drug is especially effective in the treatment of infants, as they develop the disease most rapidly. The drug can only be given once, as after it is applied, the body develops permanent immunity to the virus. It cannot be taken by people immune to this virus (estimates show that as many as 50% of adults show immunity). Currently, the drug is administered intravenously, and the manufacturer is working on a form administered by lumbar puncture, and the drug approval procedure is also underway in the European Union.

Category:

Genetic diseases