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2 new treatments for spinal muscular atrophy

The disease, the molecules and the treatments.

The disease

SMA or Spinal Muscular Atrophy is a group of genetic diseases that result in progressive muscle weakness and paralysis. It affects newborns as well as adults and can lead to the death of the patient. Generally, the earlier the onset, the worse the symptoms.

The disease affects the so called “motor neurons” of the body. These are cells from the nervous system which allow muscles to contract when activated. Typically, in SMA, the muscles of the four limbs are weakened, as well as muscles of the thorax. This leads to difficulties breathing, walking and eating. Patients show a normal intellectual development.

The inheritance (=the way the disease is acquired) is called “autosomal recessive”. Which means that the allele (or gene variant) is present in a chromosome other than X or Y; and that 2 copies of the allele are necessary to cause the disease (typically one copy from the father and one from the mother).

One person out of 50 is carrier of the genetic variant. The disease affects 1 out of 10 000 individuals. Patients need lifelong assistance, but fortunately, managing and treating the disease has improved greatly in recent years.

Max has SMA and is testing out to be a firefighter.
Before turning one year old, Max was diagnosed with SMA. Now seven, Max is a cheerful boy with a terrific smile! North Charleston from North Charleston, SC, United States [CC BY-SA 2.0 (]

The molecules

The molecule that is not working properly in SMA is a protein. Its name is SMN (for Survival of Motor Neurone). It is coded by both SMN1 and SMN2, which are genes present in the DNA. They are present on chromosome 5. We all have 23 pairs of chromosomes! SMN is present both in the nucleus and in the cytoplasm of motor neurones. There are 4 different grades of SMA which correlates roughly with the amount of SMN protein in cell nucleus.

SMN protein plays a very important role for the survival of motor neurons. In individuals affected by SMA, SMN1 is mutated and unable to code for SMN. The mutation can be a deletion or the SMN1 gene or a point mutation (the switch of a nucleotide to another). What is surprising is that most people have at least one copy of SMN2 gene, a “back -up gene” (called a pseudogene), which also codes for small amounts of SMN protein! The more copies of SMN2 one has, the less severe the disease. 5 copies of SMN2 can compensate for a setup of 2 mutated SMN1. Unfortunately, about 80-90% of the SMN2 gene product is degraded by the cell. This is because SMN2 undergoes so called “alternative splicing”, where several different mRNAs can be transcribed from one DNA sequence, resulting in different proteins. Only a small portion of the SMN protein product resulting from SMN2 results in functional SMN protein.

Chromosome 5.
Chromosome 5. Each chromosome comes as a pair, one example is from the mother, the other from the father. From the National Human Genome Research Institute [Public domain]

The business

In recent years, new groundbreaking treatments have been developed that give hope for families and patients affected by SMA. Two of them are discussed here.

The first one is Nusinersen (or “Spinraza”), by Biogen. It is the current standard of care and has an orphan drug designation in the US and the EU. It is injected around the spinal cord, which is called an “intrathecal” injection.

It is an antisense oligonucleotide drug (ASO), which means that it is made up of several nucleotides and is complementary to RNA. It acts on the alternative splicing of the SMN2 gene, thus increasing the level of SMN protein in the central nervous system.

It was first sold at 85 000 euros the injection, with six injections the first year and three the following years for 10 years, totaling $750 000 the first year and then $350 000 the next. This lifelong treatment is estimated to $4,1M dollars for 10 years and was one of the most expensive drugs on the market when approved. It had a turnover of $1,7 billion last year.

The second treatment is called Zolgensma. It is a gene therapy drug sold by Novartis, the Swiss drug maker.

It was approved by the FDA on the 24th of May 2019 and costs around $2,1M dollars, which currently makes it the world’s most expensive medicine. For 5 years, it comes out to $425 000 per year, which is 50% cheaper than Nusinersen. It treats babies up to 2 years old and is injected intravenously.

Zolgensma is comprised of a “self-complementary adeno associated virus” called scAAV9. It is a virus without the original DNA virus and a double stranded SMN1 transgene with promoters. scAAV9 can cross the blood brain barrier and reach motor neurons. Because motor neurons typically do not dividing, it is thought of as a lifelong treatment. But since no long-term studies exist, it is still unknown if this is true.

Adenovirus particles. CDC/Dr. G. William Gary, Jr. Creation Date: 1981 [Public domain]

To put things in perspective, Zolgensma is twice as expensive as Luxturna, the gene therapy developed by Spark. But Novartis promises to refund the treatment if it does not work. Turnover is estimated to $2 billion in 2022.

In conclusion, one must agree that these treatments are truly revolutionary. The use of technologies such as RNA interference for Nusinersen and gene therapy for Zolgensma where science fiction only ten years ago. Of course, they come at a pretty hefty price tag. But countries along with patient organizations and insurers are looking for ways to finance them when they get approved. And, as they most likely will get cheaper in time, the perspectives for patients affected by SMA have never looked better.

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