Could it be possible to treat babies before they are born to prevent rare diseases?

When Evelyn was born, her parents cried. A scan of the baby confirmed the news they had hoped not to receive: she suffered from spinal muscular atrophy (SMA), the same devastating disease that had already caused the death of their first child, Josephine, at just 15 months old.

SMA affects 1 baby in every 10,000-11,000 births and is a neuromuscular disease that usually causes the death of the child before the age of 3 due to a progressive weakening of the muscles, until they eventually stop breathing. It is caused by recessive mutations in a gene (SMN1), which encodes

Affected sons and daughters inherit a mutated copy from each parent, who are carriers without knowing it. Usually, parents realize that something is wrong when their first son or daughter, who they were so excited about, shows a very high neuromotor delay from almost the first month of life. These are boys and girls who will never learn to sit up alone or walk.

Since the gene involved in SMA is known, in the case of families who know that they are carriers of the mutation, they can currently choose to undergo fertilization in vitro followed by a preimplantation diagnosis to select an embryo that will not develop the disease. However, it is necessary to consider cases in families who are completely unaware of their carrier status, or recurrent cases in families who do not have sufficient information or access to fertilization. in vitro (for many reasons, economic, geographical, religious beliefs...). Thus, the only thing left for many families, when the clinical diagnosis is confirmed, is to wait for their child to die with the least possible suffering.

An experiment with gene therapy

Returning to Evelyn's case, when the pediatricians informed the parents that the girl suffered from SMA, they also proposed to them participate in a gene therapy trial. With the precedent of their first daughter, they did not hesitate and at only 8 weeks of intrauterine life Evelyn received the first and only dose of gene therapy, along with 14 other babies who suffered from SMA in 2015. This had never been seen before in any patient with SMA. In addition, Evelyn and another child could walk without any help, an incredible milestone.

The results of this first trial were published in 2017 and the development and approval by different health agencies of Two gene therapies to treat SMA, one based on the introduction of the correct gene by means of a therapeutic recombinant virus, in a single intrathecal injection (i.e. into the cerebrospinal fluid); this is the therapy that Evelyn had received. The second therapy consists of the periodic injection, also intrathecal, of a small RNA molecule that allows partial correction of the effect of the mutation in theSMN1 and produce a detectable amount of functional protein. The first aim of both therapies was to extend the life of affected children beyond two years, and the second, to demonstrate the improvement of the neuromotor system with detectable goals. Both therapies demonstrated that these two objectives could be achieved in the majority of treated children, with encouraging, but partial, improvement results.

In fact, although the patients treated with these therapies are in the first three months of life, it would be optimal to start the treatment as soon as possible, since although the function of the SMN1 protein is necessary throughout life, it is particularly fundamental for the development of the neuromotor system between the second and third trimester of pregnancy. Thus, postnatal therapy arrives when many neuromotor neurons have already degenerated.

The search for a treatment that was much more affordable (gene therapies have a very high economic cost) and easier to administer led researchers to address the search for chemical compounds. This exhaustive search attempted to "enable" the production of functional protein from another gene, theSMN2, very similar to theSMN1, which is what is mutated or completely missing in spinal muscular atrophy.

After several attempts to improve coumarin derivatives (found in the essential oils of some seeds and smells like vanilla), a very specific compound was identified that allows enough SMN2 protein to be produced. And so, as a unique milestone for now, a pregnant mother asked if by ingesting high doses of this compound orally she could prenatally treat her fetus. She obtained approval from the American drug agency and She started treatment when she was already 32 weeks pregnant..

The baby girl was born and has continued taking this medicine since the first week, and will probably have to continue taking it for the rest of her life, but the important thing is that this girl is now 30 months old and does not show any symptoms of neuromotor muscle weakness typical of SMA. In fact, this medicine has already been approved to treat orally babies with SMA from two months of age, with quite good results. It is possible that this safety trial, non-toxicity and non-development of SMA in this single case will allow the treatment of babies to advance, which implies prospects for improvement and that, in cases where it has been diagnosed for the time being, it can be given orally to the mother, as a therapy. in utero.