Gene therapy: great success against two rare diseases

Read time: 6 mins

The definition of landmark studies attributed to the two studies published in Science that report the results obtained at the Milan TIGET, respectively on metachromatic leukodystrophy and the Wiskott Aldrich syndrome, is not a daring exaggeration. Indeed, for the first time we may speak of an effective treatment against two diseases which, until now, had given little (or no) hope. The treatment combines two of modern medicine's eternal promises that had so far gone unmet and thah, having been finally put together, seem to be working: gene therapy and stem cells. Much has been said in recent months about the latter and their potential as "spare parts" as well as the many unmet expectations they created. As for gene therapy, the apparently simple idea that once the defective gene has been identified, it would be a simple matter of replacing it with a healthy one, collided with reality when, in the early Nineties, this theory began to undergo clinical experiments: on one hand it was difficult to to obtain an efficient response from the genes introduced in the body so as to produce a sufficient amount of the lacking protein, on the other, the risk of serious side effects, for example leukemia, was always lurking. However, in 1996 Luigi Naldini, current director of the San Raffaele-Telethon Institute for Gene Therapy (TIGET) in Milan, had an intuition which, while appearing as foolhardy at the time, today is proving successful: using the AIDS virus, stripped of all its pathological components, as a carrier for the genes to be introduced into the cell.

This method was used against both the diseases we are discussing today. The approach was more immediate in the case of the Wiskott-Aldrich syndrome, a haematological disease which, in addition to compromising the body's defenses and predisposing it to many other diseases, also facilitates bleeding. In this case, the hematopoietic stem cells, taken from the patient's bone marrow, appropriately modified and then re-infused, replaced the ill ones, resulting in a functional immune system and normal platelets. The task was more challenging when dealing with the neurodegenerative disease, the metachromatic leukodystrophy, in which stem cells had to get to the brain and release the correct protein in a sufficient amount such that it could be collected by the neighboring nerve cells. Nevertheless, the engineered cells worked well and, at the moment, the three children treated seem to be defying the natural course of the disease, which is marked by the progressive loss of all cognitive and motor abilities that today would have already been impaired.

Thus, inevitably, in the San Raffaele's lecture hall crowded with researchers and journalists for the press conference for these incredible results, Davide Vannoni was the "stone guest". None of the participants mentioned his name or the Stamina Foundation, but each time the metachromatic leukodystrophy was mentioned, the thought of the little girl Sofia, as this disease is now known in Italy, inevitably came to mind. "When the girl's parents turned to us, unfortunately, the disease was in an advanced stage and the girl could not be included in the study", laments Alessandra Biffi, who conducted this trial. One of the keys for this success was in fact the precocity of the treatment administered as of the first signs of the symptoms or even before their appearance, in siblings of the patients destined to get the disease: for all of them the DNA analysis in fact showed the same genetic mutation responsible for a defect in the arylsulfatase enzyme, leading to the same hopeless prognosis.  "We did not know if it would work, and we could not rule out possible risks", recalls the researcher, visibly moved and unable to hold back the joy for a result that goes beyond expectations: the three children are doing well and the benefit of the therapy is undeniable and seven others are also showing promising results, although it is still too early to declare victory.

Equally happy is Jacob's mother, one of the three children suffering from the Wiskott-Aldrich syndrome: "The diagnosis was issued when he was just four months old", said the young lady, of Indian origin, who lives on the east coast of the United States. "The only hope was a marrow bone transplant but there were no compatible donors. Then we heard about Alessandro Aiuti, and the clinical trial he was about to begin in Milan: after the treatment my son's life has changed". Before the therapy, each minor trauma caused bleeding and there was a constant risk of infection, while after the treatment both the child and his family have begun to savor the dream of a normal life, which is the dream of all those who are affected by these terrible diseases.

It is a marvelous gift that Italian research has  given to children from all over the world, thanks to the 19 million euro funding provided by Telethon. Two of them live in the United States and have made their journey of hope against the usual tide, finding a cure in Italy: a cure that has little to do with miracles but rather owes much to the work of some seventy people including researchers and clinicians who have worked hard for 15 years, not without setbacks and moments of discouragement, in order to achieve this result. "We never guaranteed such a result, not even when we showed the patients and their families on TV to ask Italian people for help, during the marathons" points out Francesca Pasinelli, Theleton's general manager. "We promised our commitment and we have been up to it" she adds. After pointing out the fact that there have never been false promises, Pasinelli emphasizes the rigorous methods applied in the research, the use of expensive but safe cell factories that conform to GMP standards, which is "good medical practice, compliance with all the steps required by regulatory authorities that, she is keen to stress, "are there for patients' protection. Indeed, no disease is so serious and no patient is in such a bad condition as not to deserve the utmost caution, and the best possible treatments". Furthermore, she points out how researchers patiently underwent strict selection processes by the independent international commission which periodically decides whether to confirm the allocation of funds and how sometimes they agreed to lengthen procedures in order to comply with the guidelines received, in order to ensure greater safety. Finally, the collected and documented data were subject to the scrutiny of one of the two most important scientific magazines in the world. Only after passing this examination, did the researchers publicly disclosed their results claiming success.

Nobody mentioned Davide Vannoni and Marino Andolina, no one mentioned the Stamina Foundation; nonetheless, everybody couldn't but notice the difference in the method of work, the rigor and and demure of these scientists and their supporters, compared with the catchwords of the expert in persuasive processes and his staff.

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