Is there a cure for Hirayama disease

Spinal muscular atrophy

Treatment of spinal muscular atrophy

Treatment of spinal muscular atrophy is complex. For a long time, causal therapy was not possible for any form of SMA. However, advances in medical research are providing doctors with new treatment options to fundamentally help those affected with proximal SMA (SMN gene defect on chromosome 5).

In addition, doctors concentrate on alleviating the symptoms and providing the best possible support to those affected (e.g. physiotherapy, respiratory therapy, psychotherapy, possibly surgery).

Gene therapy

The new treatment approaches for patients in whom the SMA is based on a known SMN gene defect intervene directly in the genetic material itself or in the downstream processing of the genetic information.

The aim is to enable the patient's body to independently produce sufficient quantities of the SMN protein, which is crucial for the motor neurons.

In the specific case of spinal muscular atrophy, the following treatment options are available:

  • Splicing modulators (Nusinersen, Risdiplam): These drugs intervene directly in the further processing of messenger RNA molecules. They strengthen those processes that deliver a higher amount of SMN protein from the intact SMN2 gene.
  • Gene replacement therapy (Onasemnogene Abeparvovec): This therapy intervenes directly in the human genome. The faulty copy of the SMN1 gene is replaced in the affected cells by an externally supplied, functional gene construct.

Splicing modulators

In the case of an SMN1 gene defect, the body can alternatively produce the SMN protein from the related SMN2 gene. The substitute gene SMN2 “jumps in”, but it only provides a fraction of the actually required amount of SMN protein. The reason is insufficient further processing of the corresponding SMN2 messenger RNA (SMN2 mRNA): A mistake during splicing - a necessary step in turning precursor mRNA into mature mRNA - results in shortened SMN proteins that are quickly broken down.

The active ingredients Nusinersen and Risdiplam prevent this incorrect processing. The administration of these so-called splicing modulators increases the amount of SMN protein per read SMN2 gene copy: The body's “yield” in the production of SMN increases - a sufficient supply of SMN protein can then be ensured.

Nusinersen

The drug Nusinersen is a so-called "antisense oligonucleotide" (ASO). It was approved by the European Medicines Agency in 2017. ASO are artificially produced and specially adapted RNA molecules. They bind specifically and precisely to the SMN2 messenger RNA. This prevents them from being further processed incorrectly in the human cell.

Specifically: Nusinersen prevents important information (exon 7) from being erroneously cut out of the SMN2 messenger RNA. The whereabouts of exon 7 causes the body to subsequently make more functional SMN protein.

Nusinersen is given through what is known as a lumbar puncture. This means that the drug is injected into the spinal canal with a syringe. This therapy is repeated at regular intervals of a few months. In the first year of treatment, those affected receive six, then three doses a year.

Patients usually tolerate the drug well. Nusinersen leads to more favorable disease courses. Studies have shown that mobility improves in many patients: in many cases, it was possible to sit freely and turn the body independently. Side effects and complications are based, among other things, on the lumbar puncture (e.g. headache, infections of the meninges).

Risdiplam

Risdiplam is taken daily as a dissolved powder. The exact dose is calculated based on age and body weight.

Approval was granted by the Federal Institute for Drugs and Medical Devices (BfArM) as part of a compassionate use program on March 12, 2020. This means that it may only be used for a diagnosed type 1 SMA if treatment with Nusinersen has previously been unsuccessful.

The requirements for the approval of Risdiplam - as part of the compassionate use program - stipulate that the manufacturer provides the drug free of charge.

Risdiplam has been extensively investigated in several clinical studies (SUNFISH, JEWELFISH, RAINBOWFISH). Risdiplam has been shown to cause rapid and sustained increases in SMN protein levels.

In the FIREFISH study, the drug was able to support important developmental stages in infants - for example, when independently holding the head and when sitting. All children were able to breathe and swallow independently.

Common side effects of Risdiplam include gastrointestinal discomfort, rash, fever, and urinary tract infections.

Gene replacement therapy

Another approach to the treatment of proximal spinal muscular atrophy relies on what is known as gene replacement therapy. The defective SMN1 gene - the starting point of the progressive SMA - is "replaced" by a new functional copy of the gene.

The one that works on this principle Active ingredient Onasemnogene Abeparvovec (AVXS-101) received conditional marketing authorization from the European Medicines Agency in 2017 for the treatment of infants and children.

The drug can be used for SMA type 1 according to EMA information. In all other forms of SMA disease, genetic characteristics (number of SMN2 copies) decide whether gene replacement therapy is an option.

With Onasemnogene Abeparvovec, a functional copy of the human SMN1 gene is introduced into the affected cells of the spinal cord and the brain stem. This is done by certain viruses that act as “ferries” for the new genetic material - so-called adeno-associated viral vectors (AAV vectors).

The vector gene constructs are given once as an infusion via the vein into the bloodstream and from there are distributed throughout the body. Due to a not yet fully developed blood-brain barrier in small children, these vectors can also get into the spinal cord tissue.

By preferentially binding these vectors to special surface structures of the motor neurons, they preferentially absorb the genetic material in order to then produce the SMN protein independently.

Treatment can improve motor functions and lead to lasting developmental success (e.g. sitting, crawling and walking without support). During the treatment, the liver values ​​may increase, but the number of blood platelets may decrease. Fever and vomiting are also common.

Age-appropriate motor development is generally only possible if gene therapy has started presymptomatically. Treatment takes place in specialized neuromuscular treatment centers.

physical therapy

Physiotherapy continues to be an important pillar of the treatment of SMA. Not every form of SMA can be treated with the new treatment approaches. Regular exercise therapy is designed to maintain physical abilities and slow down muscle breakdown.

The physiotherapist passively moves parts of the body that are already paralyzed. Active movement sequences, in turn, are trained to support the mobility and strength of the muscles. Massage or heat and cold treatments can also help. These also serve to relax and possibly slow down further degenerations.

Speech therapy

In some cases, SMA affects the speaking and swallowing muscles. Then a speech therapy exercise helps. It encourages children to learn to speak. Even in older patients, this can usually slow down a deterioration in speech. Speech therapists also train correct swallowing.

Both physiotherapists and speech therapists support those affected with targeted breathing therapy.

Pain Relieving Treatment

Pain therapy plays an important role, especially in the more advanced stages of the disease. Doctors use pain reliever medication to reduce the suffering of those affected.

surgery

Since spinal muscular atrophy can lead to severe curvature of the spine (scoliosis), doctors sometimes consider surgery. In doing so, they specifically stiffen the spine.

This gives those affected a (certain) additional torso stability, which not only enables a more upright posture, but also protects bones and joints. A spinal surgery can also help against progressive breathing problems.

Psychotherapeutic care

Neuromuscular diseases such as spinal muscular atrophy represent great psychological stress. Patients and relatives process the diagnosis in individual and group sessions led by psychotherapy and develop strategies to better deal with the disease.

In Germany, for example, the German Society for Muscle Sicknesses e.V. offers important assistance, offering those affected a first point of contact with advice, self-help groups and solving social challenges.

Read more about the therapies

Read more about therapies that can help here: