Investigational gene therapy shows early potential to treat a serious metabolic disease

An investigational gene therapy developed by researchers at theSan Raffaele Telethon Institute for gene therapy (SR-Tiget) has shown potential to treat a rare genetic disease of childhood, Hurler syndrome, which causes many disease manifestations including severely compromised growth and cognitive development and often leads to death by adolescence commonly due to cardiovascular and respiratory complications if left untreated. Strengthened by the long and solid experience on other genetic diseases, the SR-Tiget researchers have potentially corrected the genetic defect responsible for the syndrome.

In an article published in the New England Journal of Medicine they described how up to two years after treatment, all eight children treated in the study are alive and are progressing on an expected developmental path of healthy children adjusted for age and gender.

The study saw the important collaboration of a multidisciplinary team led by researchers from the San Raffaele Institute-Telethon (SR-Tiget) in Milan with clinical contribution by IRCCS Ospedale San Raffaele, experience in study and treatment of this pathology by the San Gerardo Hospital in Monza, statistical analysis by the Bicocca University ,and biochemical studies by the Meyer Hospital of Florence.

What is Hurler syndrome

Hurler syndrome, also called mucopolysaccharidosis type 1H, or MPS-IH, is due to the lack of an enzyme that  degrades particular sugars, called glycosaminoglycans, which accumulate and can damage the cells of different organs. The incidence of MPS-I is estimated to be one case per 100 thousand newborns globally. Hurler syndrome is the most severe subtype and represents approximately 60 percent of all MPS-I cases. MPS-IH  is considered an ultra-rare disease—there are currently there are about 400 living cases in the world, 26 in Italy.

The investigational gene therapy provides the potential to insert a corrected version of the genetic information needed to produce the missing enzyme. Hematopoietic stem cells, which give rise to blood elements such as red and white blood cells or platelets, are first taken from the patient. The patients' cells are then put in contact with a viral vector, a virus modified so that it is no longer able to replicate, but only to enter the cells and insert the desired genetic information. The starting virus used by the researchers is HIV, the agent responsible for AIDS.

In recent years, vectors derived from HIV, of which they maintain only a small portion of the original sequence, are increasingly used as therapeutic tools and in this sense the San Raffaele Institute-Telethon is a leader in the world: of all patients with rare genetic diseases treated today in the world with this type of vector, called lentiviral, a third received treatment in Milan. Once corrected, the stem cells are returned  to patients through an infusion into the blood, and after differentiating into blood cells, can reach the various organs, where they release the functioning enzyme capable of degrading otherwise toxic substances.

The first promising results

"The effects of this investigational gene therapy on the metabolism of these children were seen within months,” commented Maria Ester Bernardo, head of the pediatric bone marrow transplantation functional unit of the San Raffaele Hospital and one of the main authors of the study. "Their cells began to produce the enzyme, which cleansed organs and tissues of accumulated toxic metabolites. From a clinical point of view, we have observed the progressive acquisition of new motor and cognitive skills typical of their age, as well as  an excellent growth in height and a  reduction of other typical symptoms of the syndrome such as joint stiffness and opacity of the cornea. Caution is a must: only two years have passed since the therapy, we will have to continue to observe these children to verify that the positive effects  continue over time. However, these data observed so far gives us hope."

This gene therapy approach is the result of more than ten years of SR-Tiget research, in which Bernhard Gentner, head of the  translational stem cell and leukemia research unit and first author of  the newly published study, played a crucial role. Among the key factors was the previous successful experience on another genetic disease due to the accumulation of "undisposed" toxic substances, metachromatic leukodystrophy. "Our gene therapy process has allowed us to increase the amount of functioning enzyme produced up to 50 times compared to normal levels," commented Gentner. "This could also potentially have a further advantage over hematopoietic stem cell transplantation, which to date is the only treatment that can partly improve the course of the disease, provided it is done early and in the presence of a compatible donor. At the moment, however, we still do not have enough data in this regard, we need more time.”

Alessandro Aiuti, deputy director of SR-Tiget and full professor of Pediatrics at the Vita-Salute San Raffaele University, who coordinated the study, concluded: "The path is still long but it is encouraging that the development times of these therapies are shortening thanks to the experience accumulated in recent years. It will thus be possible to broaden the horizon of diseases potentially treatable with gene therapy with correct blood cells as a "super factory" of the missing enzyme in various tissues, thus replicating this approach to other similar pathologies that today do not have an effective cure.”


About the alliance between Telethon, San Raffaele and Orchard Therapeutics


The San Raffaele Telethon Institute for Gene Therapy in Milan (SR-TIGET), directed by Prof. Luigi Naldini,  was born in 1995 thanks to a joint venture between the San Raffaele Hospital, a clinical-scientific-university structure of international importance and high specialization, and Fondazione Telethon, one of the main Italian charities in the biomedical field. SR-TIGET is today an international reference point for research on gene transfer and cell transplantation for various genetic diseases. To transform research results into therapies for patients, in 2010 Fondazione Telethon and San Raffaele Hospital signed a strategic alliance with GlaxoSmithKline (GSK), to combine research skills with the development capabilities of the pharmaceutical industry. The goal of the alliance was to make gene therapy available for 7 rare genetic diseases, including ADA-SCID immunodeficiency, for which the first ex-vivo gene therapy, Strimvelis, was approved and marketed in 2016. In 2018, GSK transferred its gene therapy portfolio to Orchard Therapeutics, a British biopharmaceutical company focused on hematopoietic stem cell gene therapy. In December 2020, the gene therapy for metachromatic leukodystrophy, Libmeldy® (atidarsagene autotemcel), was approved by the European Commission. Orchard Therapeutics' portfolio also includes investigational gene therapy programs for Wiskott Aldrich syndrome and mucopolysaccharidosis type 1H.