Why I suffer from the most beautiful disease in the world (and the most expensive to treat)

My name is Antonio and I have spinal muscular atrophy (SMA, for friends). My life expectancy was a few years when I was born, almost half a century ago. And all because I “touched” a rare, neurodegenerative disease, which is among the genetic diseases with the highest associated mortality.

What happens, explained in a simple way, is that my motor neurons (the “cables” that connect the spinal cord with the muscles) gradually degenerate and end up dying. This has had me sitting in a wheelchair for most of my life. And over time, the involvement of the respiratory muscles can lead to a fatal outcome.

But since I am also a scientist, to all of the above I must add that I have discovered that SMA is the most beautiful disease in the world… at the molecular level.

How does spinal muscular atrophy occur?

SMA is a genetic disease caused by the mutation or loss of a gene called SMN1. If our mother and father have a mutated copy (one of the two copies each has), and we are unfortunate enough to inherit these two defective copies, we most likely have SMA.

This gene contains the information to guide the construction of a protein called SMN. Its name comes from the suggestive initials of English survival of motor neuron (motor neuron survival), and performs very important functions in our body. In fact, without SMN, motor neurons do not survive, nor is there the possibility of life itself. This is because these cells are essential for carrying out muscle movements, including those of the diaphragm or pharynx, which allow us to breathe and eat.

But then how do we SMA patients survive? Well, because it turns out that in the human genome there is a second gene, called SMN2which also makes it possible to build that same SMN protein. SMN1 and SMN2 they are almost identical, but SMN2 it is distinguished by five of the more than 40,000 letters or nucleotides that make up these genes.

The existence of practically identical genes is something very rare in the human genome. In fact, SMN2 it does not even exist in other animals: it is unique to our species.

a life saver

These minimal differences between the two genes make the SMN protein from SMN2 It only occurs completely in 10% of cases. In principle, this would be insufficient to live in the long term, but it happens that human beings can have from zero to more than ten copies of the gene. SMN2.

Doing a quick calculation, if we have ten copies, and each one produces 10% of SMN, we will generate 100% of the SMN protein that we need. But what if we have fewer copies of SMN2Let’s put five? Well, only 50% of the necessary SMN is compensated.

Thus, in general, those who lack the gene SMN1 and have only one copy of SMN2 have a severe case of the disease, with more rapid progression (type I). Those who have two copies suffer a milder case (type II). Finally, with three or more copies we have an even milder case (type III) and the chances of living longer are extended.

Given this reality, we can conclude that evolution “was invented” SMN2 in humans (the copy of SMN1) to have a lifeline in case of losing the main gene. Nice, right?

Treatments at exorbitant prices

Knowing everything we know, how can we cure SMA? if missing SMN1 or the gene is mutated, as happens with other genetic diseases, there is no other option than to replace the missing gene. In fact, although it sounds like science fiction, this substitution is something that is already done. In 2019, the drug Zolgensma was approved, which allows the introduction of the gene SMN1 through a virus that takes it directly to motor neurons.

But the real beauty of SMA is that, because there is SMN2, we can use other more original approximations. Let’s think about it for a moment: if we can figure out what makes SMN2 only produce 10% complete SMN protein and we repair the problem so that the percentage is higher, we can compensate for the lack of SMN1. And that is what the first treatment approved in 2016 against SMA, Nusinersen, does, and also another one approved in 2020, Risdiplam.

What these treatments achieve seems really easy to do with some basic biology. In the case of Zolgensma, it is about carrying the gene SMN1 intact up to the motor neurons, which is currently called gene therapy. And in the case of the other two treatments mentioned, the challenge is to get something to stick to the region that differentiates SMN1 and SMN2to make the second the first.

But the difficulty of making this work, and also bringing it to the market for rare diseases, makes both treatments among the most expensive in the world. Zolgensma costs nothing less than… two million euros per dose! That makes it the most expensive disease in the world. Fortunately, only one dose is required. In the case of Nusinersen and Risdiplam, their cost would range between 400,000 and 800,000 euros per year (and, of course, per patient).

What are these sidereal prices due to? The easy answer is that we will never know. Pharmaceuticals usually negotiate the price of the drug independently in each country and with zero transparency. This leads them to consider the drug as a commodity, the price of which does not have to be linked to its development and production cost. Rather, it is the price that is willing to pay for the life and well-being of patients in every part of the world.

And I forgot something important: none of the three medicines cure. They only slow down the progression of the disease – which is no small thing.

Future for SMA and other rare diseases

What will happen in the future with these treatments against rare diseases? Well, obviously, the market will end up making prices cheaper. Treatments such as gene therapy have already been used for other diseases, and will undoubtedly continue to appear and, most importantly, to be perfected. Finally, the universality of its use will favor lower prices.

On the other hand, we can place our hopes in the repositioning of drugs, that is, the use of existing drugs for other diseases. It has the enormous advantage that it greatly reduces costs and allows shortening research times.

In conclusion, it is indisputable that SMA is a devastating disease, and that SMA patients will always have the right to complain about the bad luck we were born with. But, at least, I hope I have shown that this disease has a special charm at the molecular level that, for those of us who suffer from it, also gives us a certain right to label it as “the most beautiful disease in the world.”

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