Gene therapy for Hurler syndrome, a rare disease that leads to the accumulation of toxins in many organs with severe bone damage, appears to restore, at least partially, the skeletal growth of children affected by it. In fact, for the first time, the effects of this approach on the alterations of the bones and joints of the first 8 children treated are published, 4 years after the infusion of the therapy. This is a new analysis of the phase I-II clinical study developed in 2018 by Tiget – Telethon Institute for Gene Therapy of San Raffaele in Milan, and the data are presented on Science Translational Medicine.
Skeletal diseases in children: to study them, a 3D bone model
at Emanuela Pasi
What is Hurler syndrome
Hurler syndrome is the most serious form of mucopolysaccharidosis type 1. The mutation of the IDUA gene leads in fact to the deficiency of a very important enzyme for cells: the consequences are progressive damage to the skeleton, heart, liver, spleen, to the muscles, the nervous system, the eyes, the hearing. In the absence of treatment, survival is around 10 years, while with a transplant from a hematopoietic stem cell donor, which currently represents the standard of care, it can reach 20-25 years, but disabilities have a very heavy impact on quality of life.
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The results of the study
“In these 4 years of follow up – explains a Salute Maria Ester Bernardo, principal investigator of the study – we observed that the children treated with gene therapy are developing, from a skeletal point of view, in line with the normal growth curves of healthy subjects. All underwent therapy when they were between 14 and 35 months old. Through x-rays and magnetic resonance imaging, we were able to observe a stabilization and, in some cases, an improvement in skeletal alterations, including those of the hips and spine. Furthermore, we have observed that joint stiffness, which prevents these children from carrying out normal daily activities such as dressing or brushing their teeth, resolves completely in a short time. We do not yet know whether these results are long-lasting or not: these are preliminary data which will need to be confirmed in the next 4-5 years, but which give us great comfort. Furthermore, compared to a similar cohort of patients external to the study and treated with allogeneic haematopoietic stem cell transplantation, gene therapy seems to provide additional benefits: obviously this is a retrospective comparison which has many limitations from a scientific point of view, but which gives hope.”
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More copies of the correct gene
In allogeneic transplantation, healthy hematopoietic stem cells from a donor replace those with the patient’s defective IDUA gene, and begin to produce the corresponding enzyme in a “normal” amount. However, this does not seem to be sufficient to completely stop the damage from the accumulation of toxins and, therefore, the progression of the disease. “With gene therapy, however – explains Bernardo – the patient’s stem cells are modified by inserting one or more copies of the correct IDUA gene into them, so that they can express levels of the enzyme up to 5 or 10 times higher than normal. Based on the results obtained so far, it seems that in this way gene therapy can induce a more effective metabolic correction of the damage. In particular, we expect a good response in bone cells, because some of these derive from hematopoietic stem cells: the systemic effect could therefore also be associated with a local effect, at the level of the microenvironment”.
A new clinical study
The true comparison between the effectiveness of allogeneic transplantation and that of gene therapy will only be possible in a few years, when the results of a phase III clinical study which has just started and which involves 6 centers at an international level will be mature: three in the USA and three in Europe, including the Tiget. This trial is funded by the company Orchard Therapeutics, which received the gene therapy license for Hurler syndrome in late 2019.
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The importance of newborn screening
In any case, both for allogeneic transplantation and for experimental gene therapy, the time factor is crucial: since it is an accumulation disease, the sooner one intervenes, the greater the benefits can be. “The disease is present from birth but, being rare, the average age at diagnosis is 18 months – underlines the expert – The tell-tale sign is often kyphosis which leads to referral to an orthopedist. The widespread diffusion of neonatal metabolic screening – she concludes – would make it possible to eliminate delays in diagnosis and intervene early”.
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– 2024-05-06 10:46:34
