Is SMA deadly

Spinal muscular atrophy: Using viruses to repair diseased genes

It took a long, very long time. But 20 years after the genome was deciphered, the time has finally come. Genetic diseases that have so far been fatal can be treated through targeted manipulation of the genetic make-up.

To do this, manipulated viruses are sent into the body that paralyze pathogenic gene segments and replace them with intact ones. Scientists have worked at full speed on this vision over the past two decades - for a few diseases this is now becoming a reality.

One of them is spinal muscular atrophy (SMA), specifically: its most severe form with the diagnostic designation SMA-1. Babies born with a genetic defect on chromosome 5 have short lives. While in healthy children the so-called motor neurons ensure that infants learn to hold their heads upright, to sit, to stand and finally to walk in the first two years of life, this development simply does not take place in SMA children. Your organism lacks a key protein, namely that for the development of motor neurons.

Lack of muscle tone

Paediatricians like G√ľnther Bernert, head of the Department of Pediatrics and Adolescent Medicine at the South Social Medicine Center, usually notice this very soon due to the babies' lack of muscle tone right after birth. The hereditary disease is also called floppy baby syndrome.

"There are always terrible fates," says Bernert, who has looked after some of these patients in his long career. Spinal muscular atrophy is a rare condition with different forms (see knowledge below). One in 10,000 children is affected. And their parents always had no idea that they were carriers of a genetic mutation.

The condition of babies with SMA gets worse as the months go by. If the nerve cells do not transmit impulses to the muscles, they atrophy. The disease also makes swallowing and breathing increasingly difficult - the children usually suffocate before they have reached the age of two.

A drug that can stop such a tragic and fatal course with a single infusion is therefore a real medical sensation. Zolgensma is the awkward name for a gene replacement therapy developed by the pharmaceutical company Avexis, a subsidiary of the Swiss pharmaceutical giant Novartis.

An infusion

It is actually less of a drug and more of a specifically modified virus that controls the motor neurons in the spinal cord, penetrates the cells and leaves healthy genes in the cell nucleus. The body can then make the protein that SMA patients lack.

Babies who receive this therapy immediately after birth even develop in almost the same way as healthy children. Your nerve cells fire impulses, the motor neurons pass these on to the muscle fibers, which in turn grow and enable the children to sit, stand and learn to walk.

Zolgensma has been approved in the USA since May 2019 and in the EU since mid-May. The results of the clinical studies showed how well the gene replacement therapy works. Around 400 children worldwide have benefited from this revolutionary form of treatment. "The earlier you get the therapy after the birth, the more normal your development. This is really a breakthrough," says pediatrician Bernert.

A single infusion is sufficient, and side effects can be easily managed. And all in all, it would all be worth cheering. But there is one major drawback - and that is the cost of the therapy. A single necessary dose of gene replacement therapy costs almost over two million euros. SMA is a rare disease, but such therapy costs have what it takes to blow the budgets of solidarity-funded health systems.

Harmless cold viruses

The fact that viruses change the human genome is a fundamental principle of evolution. In recent years, scientists have found out how, for example, harmless cold viruses can be manipulated in such a way that, firstly, they do not trigger a cold and, secondly, they can act as a kind of means of transport for new genetic information.

So-called adeno-associated viruses (AAV) carry a replica of the functioning gene that SMA children lack. They find the motor neurons, dock on, and the production of the corresponding protein starts. What sounds kind of simple is the result of long and tenacious research in which different approaches have been taken with different viruses.

The production of this gene replacement therapy is also many dimensions more expensive and complicated than conventional drugs. After all, one works with the modular system of evolution - the production of the infusions itself is also pioneering work.

The sooner the better

And because we are breaking new ground not only therapeutically, but also at the production level of such drugs, the Zolgensma gene replacement therapy is only approved in the USA for children with SMA-1 up to the age of two, because - as clinical studies have shown, - benefit a lot from it.

Since Zolgensma is most effective immediately after birth, many paediatricians are in favor of checking all newborns for a mutation on chromosome 5.

However, one of the distinctive features of the genome is its diversity. Genes are regulated differently from person to person. That is also the reason why diseases take different courses. 60 percent of all SMA patients have the severe form, SMA-1, but 40 percent have a lighter variant, which means that they produce the protein that is necessary for nervous and muscular development, but not in sufficient quantities.

"Although spinal muscular atrophy is a monogenetic disease, there are minimal differences in regulation that result from the various alleles," explains Wolfgang Schmidt, geneticist at the Institute for Anatomy and Cell Biology at the Medical University of Vienna.

For the less severe forms of SMA, a drug that boosts gene expression of the missing protein has been approved since 2016. Spinraza is injected into the spinal cord using a lumbar puncture. Although this weakens the disease, it cannot be reversed.

"However, gene replacement therapy could also be an option for this group of patients, even if the results would not be as impressive as with an early dose," says Bernert. From a medical point of view, Zolgensma would also be an alternative to the currently approved therapy with Spinraza.

And this therapy, which has already been approved, is expensive: the therapy costs 600,000 euros in the first year of life, and 300,000 euros each additional year, depending on the child's condition. "There are different therapies, so you can't compare them at all," says Hardo Fischer, medical director of Avexis Austria, who also compares the prices. After the first seven years of life, the two therapies are the same in terms of costs.

The crux of the matter is costs

In the end, it is the high costs that sparked a discussion in Germany. A lawyer sued the right to the new drug for SMA sufferers. Since the drug still has to be approved in Europe - and then only for the patient group up to the age of two - there was fear of delivery bottlenecks due to the complex production.

Without further ado, the parent company decided to make 100 doses of the drug available in the form of a managed access program, which means that patients get it free of charge. An external ethics committee should decide which patients are selected. At the beginning of February, rumors suddenly circulated that Novartis was holding a kind of lottery for marketing purposes for gene replacement therapy.

"This action was never planned that way," says Hardo Fischer and admits that it was not communicated in enough detail or in sufficient detail. They only wanted to make this therapy available to affected families - even if the health systems in which these people are insured cannot afford the sum of almost two million euros.

After years of development and research work, it could be that a new type of drug that can stop a fatal disease may not even be used because it fails to finance. "We currently still lack the production capacities for broad use before approval," emphasizes Fischer once again.

A side effect of gene therapy seems to be that it also raises very unexpected ethical questions for which the system does not seem to be equipped. The corona crisis will not improve the situation. (Karin Pollack, CURE, June 7th, 2020)

Update: This article appeared in Cure, Standard's health magazine, on April 4th and is only now being published online. In mid-May, Avexis received approval for the drug Zolgensma (active ingredient name: Onasemnogene Abeparvovec) in Europe. Children born with SMA 5q and a biallelic mutation in the SMN-1 gene and up to three copies of the SMN-2 are eligible for therapy.

The manufacturer Roche recently published new data on the effectiveness of Risdiplam. The effect of the drug is documented in the Firefish Study Part 2. Approval for the drug is planned for 2021.

Original publications:

Onasemnogene Abeparvovec-xioi Gene-Replacement Therapy in Presymptomatic Spinal Muscular Atrophy: SPR1NT Study Update

FIREFISH Part 2: Efficacy and Safety of Risdiplam (RG7916) in Infants with Type 1 Spinal Muscular Atrophy

Knowledge: Forms of gene therapy and the problem with SMA

There are four approaches to treating monogenic disorders. At the Gene replacement If a faulty gene is replaced by a healthy one, a manipulated virus is smuggled into the body. In the Gene addition a new or modified gene is introduced against the disease. In the Gene inhibition a mutated gene is inactivated in a Gene editing the gene sequence is changed in a targeted manner with the Crispr / Cas9 gene scissors.

Genetics of SMA Disease

In the course of human evolution, a certain section of chromosome 5 has doubled, and two almost identical genes have emerged. While that SMN1-Gen produces correct, complete proteins is provided by the SMN2-Gen usually only produces a shortened, incomplete protein. If both parents have a defective SMN1 gene on chromosome 5, they will not notice anything, because there is an intact SMN1 gene on the second chromosome 5. If the child gets chromosome 5 from both parents without an intact SM1 copy, it will develop SMA.

There are four different forms of the disease: SMA type 1 is the most common and most severe form at 60 percent and is discovered in the first six months of life. In milder forms such as SMA type 2 the protein that is responsible for maintaining the motor neurons is not produced in sufficient quantities. The disease begins in the first year of life, only sitting is learned SMA type 3, mostly diagnosed in childhood, those affected can walk without help. SMA type 4 occurs in adulthood, the muscles recede. (Karin Pollack, CURE, June 7th, 2020)

Read on about gene therapies:

How the body could defeat cancer on its own

Researchers are developing gene therapy for HIV infection

The genome is not an open book