Over time, scientific progress has given us new directions, including that which points to a wide range of possibilities in the field of genetics. The analysis of individual and collective genetic data as a diagnostic tool in order to adapt health care more accurately is a reality in modern times. And despite the ethical discussion it raises, gene therapy is nowadays seen as a very promising practice, resulting from extensive research and technological innovation applied to health.
Genes have been at the centre of the research conducted by Professor Maria do Carmo Fonseca, specialist in genetics and molecular biology, and Head of the IMM Genetic Regulation Laboratory.
In addition to believing that, over time, we will have genetic therapies "safe enough" to slow the ageing of human cells, the Professor is a staunch supporter of their use in other areas of medicine. In recent interviews, Carmo Fonseca explained how gene therapy, as well as the research projects that have been carried out in this context, can be decisive in the diagnosis and treatment of various diseases, namely cancer and some cardiovascular pathologies.
"For a long time, we thought that what we inherited from our parents was more or less a fate engraved in the genes. It is not like that, we have the capacity to act on them. The basic information is not necessarily a fatality", highlighted the Professor in an interview on the topic.
And Carmo Fonseca's fascination with the universe of human genes has led us to Paediatrics at Santa Maria Hospital, where the fatal sentence of a rare degenerative neuromuscular disease is reversed with the use of gene therapy.
We talked to Dr Teresa Moreno, a neuro-paediatrician responsible for gene therapy for Spinal Muscular Atrophy, in close collaboration with the Paediatric Pulmonology, Rehabilitation, Gastroenterology, Nutrition, and Paediatric Surgery team. We now understand what this disease consists of, how it is transmitted, how it manifests itself and how medicine evolved in response to what is currently the main genetic cause of death.
What is Spinal Muscular Atrophy and how is it characterized?
Teresa Moreno: It is a neuromuscular, degenerative, autosomal recessive disease. The parents are healthy carriers and in 25% of pregnancies there is a risk of the disease arising. It is also the most severe and frequent recessive genetic disease in children and it has an incidence of approximately one case in 6,000-10,000 live births.
It is a disease that is characterized by progressive loss of motor nerves. The nerves that control our muscles begin to degenerate and die throughout the child's life. The problem originates in the body of the motor nerve cell that is located in the spinal cord, which is why it is called Spinal Muscular Atrophy, because it is in the anterior horn of the spinal cord that the cell bodies that start to die are, with the degeneration of the axons that stem from there.
How does the disease manifest itself? Is it similar in all cases?
Teresa Moreno: It is a disease that has a very noticeable genetic peculiarity. This disease, despite having the same mechanism in all its types, has very different types according to the severity. For the disease to manifest itself, it is necessary to have the absence of a gene called SMN1, which is the motor neuron survival gene. This gene is so important that its nonexistence is not compatible with survival. So, in this case, Nature, throughout evolution, created a copy called SMN2, which we all have. However, the number of SMN2 copies varies from person to person. In short, the disease is evident when children do not have SMN1. On the other hand, SMN2 is an imperfect copy, since 85% of the protein is not viable and is of no interest to the body. The other 15% are. So if we have a copy of SMN2, we have 15% normal protein, if we have two copies we have 30%, and so on.
Thus, although not everyone has SMN1, the severity of the disease will be determined by the number of random copies a person has in his or her genome. In fact, the most serious phenotypes have only two copies of SMN2, while less serious phenotypes have four or five copies of SMN2.
Is this what will define the degree of severity of the disease?
Teresa Moreno: The type of disease is always defined by the highest motor stage reached. Classically, and it is a disease that was described in 1891, Spinal Muscular Atrophy is divided into clinical types. There is Type 1, which manifests itself in the first months of life and never reaches the sitting position. Type 2 are children who reach the sitting position, but never achieve an independent gait. Type 3 are children who reached independent walking, but lost it afterwards, and these cases are very variable. They may lose their gait at 3 or 18 years of age, and the age of the onset of the disease is also different. There is also a rarer Type 4, corresponding to less than 5% of cases, which appears in adulthood (around 30-40 years of age) and patients never loses their gait.
It is a complex disease that requires the monitoring of several specialties, isn't it?
Teresa Moreno: All these cases need multidisciplinary follow-up. All patients l have respiratory failure requiring night ventilation, since the respiratory muscles gradually lose their functionality, and in some cases doctors administer prophylactic non-invasive night ventilation. The survival of these children has increased immensely since the beginning of ventilation, because they died of respiratory failure, and since the moment when, 15 years ago worldwide, multidisciplinary standards of care were established for intervention in ventilation, nutrition, and therapy aggressive surgical treatment of scoliosis, children managed to survive with a better quality of life and normal school life, in a wheelchair, it is true, but the disease does not affect the cognitive part, so they are brilliant kids, with a great motor handicap and who, at the same time, are very interesting and challenging.
And when did gene therapy begin to be used?
Teresa Moreno: When it was possible to concretely understand the genetic problem, an attempt was made to find a solution. Until recently, there was no treatment, but in the past four years, three drugs have been approved to modify the disease. This gene therapy performed in Spinal Muscular Atrophy was the first gene treatment approved in the world for any disease. The first drugs that appeared, and many are still at clinical trial stage, resulted from the correction of the small defect in SMN2 with a view to the production of the complete protein. This was the first medication approved in December 2016, called Nusinersen, and does not act at the level of the gene, but at the level of messenger RNA, that is, in the splicing of the gene, correcting that error and causing the protein produced to be complete. And the results were very exciting for those who work with this disease. Type 1 cases have a mortality rate of almost 95% before the age of two, 80% in the first year of life, so whoever saw many children die suddenly has something to offer.
However, Nusinersen has the disadvantage of being administered by lumbar puncture. It is a spinal cord injection that is done initially at 0 days, at 15 days, at 30 and 60 days and afterwards at every 4 months for life. This, not being the one we call true gene therapy, has been used in our children here in Paediatrics.
At the moment, a drug with the same action mechanism, Risdiplam, has been approved in the United States. The technique is different, since it is administered orally. We now hope that it will also be approved in Europe.
Does real gene therapy come later then?
Teresa Moreno: Yes, it was approved in 2019, in the United States, and in 2020 by the EMA. The real gene therapy consists of introducing the missing gene, the SMN1. A virus, an adenovirus, has been modified in order to be able to transport the gene into the nucleus. We "infect" the child with millions of copies of a gene carried by a virus, which is not infectious in itself, since its ability to replicate has been removed.
And how is this therapy performed in practice?
Teresa Moreno: Intravenously, only once, since the virus takes the gene to the nucleus and, despite not inserting itself into the genome, it remains autonomously within the nucleus and replicates itself repeatedly. Five years after the first treatment in clinical trials, the action mechanism remains effective. In our Service here in Santa Maria, we started to use gene therapy in 2019. So far, we have already use it in nine patients in Portugal, five of whom at Santa Maria Hospital (two in 2019, three in 2020) and we were almost precursors at European level. In fact, we were the first country in Europe, outside the clinical trials, to introduce this therapy.
At the moment, do you resort just to gene therapy for the treatment of Spinal Muscular Atrophy?
Teresa Moreno: No, we also do intrathecal injections - which is part of the group of disease-modifying therapies - because the authorization of the EMA limits gene therapy, at this moment, to the smallest infants, that is, children up to 21 kilos with two or three copies of SMN2.
Clinical trials have only involved children up to 8 and a half kilos and the EMA has issued an authorization that has astonished the entire scientific community, because it has allowed children up to 21 kilos to be treated. There are no studies in children of this weight, they are now planning clinical trials to prove that it is also effective in older children. The big problem lies in the viral load that is injected, per kilo, into such heavy children, raising the question of whether or not it is tolerated by the body.
Which of the therapies is most effective or appropriate?
Teresa Moreno: They are all successful, because they all modify the evolution of the disease. As for the medication - whatever it is – it is more effective when it is started at an earlier stage. It is a neurodegenerative disease that causes an abrupt loss of motor neurons in the first 3 months of life, and since they are body cells that neither reproduce nor regenerate, they are lost forever. Thus, when therapy is done early, it can almost perform miracles.
What is the investment involved in these therapies?
Teresa Moreno: In the case of Nusinersen, about 100 thousand euros each dose, and gene therapy costs 2 million euros. Obviously, in order to justify these costs, treatment needs to take place as soon as possible, in order to guarantee a normal life.
The struggle that we are now waging, which is taking place in some European countries (Germany, northern Italy and others), is to introduce the diagnosis of Spinal Muscular Atrophy in the Guthrie test. This enables treatment before the first symptoms.
In clinical trials that are doing pre-symptomatic gene therapy, all children are walking and have motor steps just like a normal child, so it is all worth it.
Over more than 20 years of activity dedicated to Neuro-paediatrics, Teresa Moreno has witnessed the loss of more than two dozen lives that, in the absence of a cure or other viable solution, had the only and the most unhappy of the outcomes to date. However, these days, the evolution is different and Teresa Moreno recognizes, with evident enthusiasm, that "watching this revolution makes us very happy".
How has the evolution of these children been, after gene therapy?
Teresa Moreno: Our children are not cases in which we expect, miraculously, that they start walking from one day to the next. The longest follow-ups take place 18 months after therapy, and it is true that they are children who are already standing and are starting to take their first steps.
What are their ages?
Between 18 months and 2 ½ years. They are children who normally would have died, according to the natural evolution of the disease. However, today they are already starting to eat using their mouths, talk, stand up, take their first steps with support and all this is very rewarding. Obviously, something very important, even for the older ones (who continue to take Nusinersen), was to moderate expectations, even for the children themselves, since they started treatment at an advanced stage of the disease. The disease cannot be reversed, so the idea is that it does not get worse and progresses to quadriplegia, so that they can be independent, even in a wheelchair.
Nobody has long-term results, because everything is very recent worldwide, so these patients have a very close follow-up. The scientific community needs to understand how they evolve in the long term, if the medication continues to be effective, what will happen to the respiratory function, if they will no longer need ventilation... Everything is unknown and the future is completely open in this area.
Teresa Moreno believes that the future of Medicine involves gene therapy, "although not all neuromuscular genetic diseases, and there are many, have effective results". "The good thing about Spinal Atrophy is that the gene is very small, it is transportable", she explained, noting that "there have been other attempts with transport vehicles other than viruses, but they have not been effective".
Currently, the Paediatrics Service of Santa Maria Hospital follows up five children with Type 1 Spinal Muscular Atrophy, who have undergone gene therapy, in a post-symptomatic context, who require permanent care based on a multidisciplinary intervention throughout their lives.