The research carried out at our Institutes has pinpointed promising therapeutic strategies for combating a number of diseases. Such results are the result of years spent investigating the mechanisms underlying genetic diseases, and developing innovative forms of treatment. Concrete answers are now emerging for all patients.

Marketed treatment

Ada-Scid

ADA-SCID is one of the first inherited diseases to be successfully treated with gene therapy. Thanks to the research conducted at the San Raffaele-Telethon Institute in Milan, an effective gene therapy has been developed to counter this serious immunodeficiency disease that appears early on, in the first months of life. It manifests as recurrent, aggressive infections. The trial therapy was administered to patients all over the world. It was found to be both safe and capable of restoring immune system functions. Thanks to an agreement stipulated with GlaxoSmithKline, and now licenced by Orchard Therapeutics LTD , the outstanding results obtained by researchers at the San Raffaele Telethon Institute for Gene Therapy in Milan have been turned into a marketed treatment: Strimvelis.

Clinical trial

Metachromatic Leukodystrophy

Metachromatic leukodystrophy is a very serious neurodegenerative disease. In this case, gene therapy is exceeding our wildest expectations. Thanks to research conducted at the San Raffaele-Telethon Institute in Milan, in 2010 a clinical trial was set up involving patients from all over the world suffering from this serious genetic disease. Additional patients have been treated under  an expanded access program and with a cryo-preserved formulation. A new study is also ongoing on late juvenile patients. Metachromatic leukodystrophy leads to a gradual loss of all cognitive and motor capacities. At present, there is no effective treatment, but the preliminary results have been most encouraging. So far, gene therapy has been shown to be capable of safely preventing the onset of this disease. If these results are confirmed over time, it will be possible to make this therapy available to all patients worldwide, thanks to an agreement stipulated with GlaxoSmithKline initially and now with Orchard Therapeutics LTD.

Wiskott-Aldrich Syndrome

This rare immunodeficiency disease targets males. Onset occurs already during the first months of life. Thanks to research conducted at the San Raffaele-Telethon Institute in Milan, a clinical trial was initiated in 2010, involving patients from all over the world suffering from this immunodeficiency disorder which is characterised by recurrent, aggressive infections and a tendency to haemorrhages, blood tumours and autoimmunity. Additional patients have been treated  under  an expanded access program and with a cryo-preserved formulation. The first results have been most encouraging. So far, gene therapy has also been shown to be capable of safely restoring these patients’ immune defences. If these results are confirmed over time, it will be possible to make this therapy available to all patients worldwide, thanks to an agreement stipulated with GlaxoSmithKline initially and now with Orchard Therapeutics LTD.

Thalassaemia

Thalassaemia is one of the most frequently occurring hereditary diseases. It is particularly frequent in the Mediterranean basin area. Thanks to research conducted at the San Raffaele-Telethon Institute in Milan, a clinical trial was started in 2015 involving patients with a hereditary haemoglobin defect. The only treatment available to date for such patients is bone marrow transplantation (which is not always possible) or transfusion (to be performed on a regular basis, with concurrent administration of medication to prevent toxic accumulation of iron). The study involves adults and children.

Mucopolysaccharidosis type 1

Mucopolysaccharidosis type 1 is a metabolic disease affecting infants. It targets various organs, including skeleton and heart. Thanks to research conducted at the San Raffaele-Telethon Institute in Milan, a gene therapy has been developed in the laboratory that may be able to correct the genetic defect at the root of this condition. The only treatment available to date is bone marrow transplantation. However, this treatment is only partially effective. The clinical trial on patients started  in 2018.

Mucopolysaccharidosis type 6

This is an extremely rare disease, targeting above all the skeleton, eyes and heart of infants. At present, the only available treatment is enzyme replacement therapy, which is not entirely effective. Thanks to research conducted at the Telethon Institute in Pozzuoli, gene therapy has been developed in the laboratory that could correct the genetic defect at the root of this disease. At present, the only available treatment is enzyme replacement therapy, which is not entirely effective. A clinical trial with patients started in 2017, in collaboration with the university hospital of Naples Federico II.

Pyruvate Dehydrogenase Deficiency

This metabolic disease causes retarded psychomotor development. The therapies currently available include a ketogenic diet and administration of thiamine and dichloroacetate. Researchers at Tigem in Pozzuoli recently demonstrated the therapeutic potentials of another drug, phenylbutyrate to increase residual activity of the enzyme, of which there is a deficiency in these patients. A pilot clinical trial is ongoing to test this hypothesis.

Type 2 Glycogenosis

This metabolic disease, also called Pompe disease, targets the muscles, weakening them and undermining their functionality. The only treatment available at present is periodic administration of the missing enzyme. In 2011, Telethon funded a clinical trial at the “Federico II” University in Naples aimed at improving the effectiveness of the enzyme treatment that is currently available for this disease. Researchers at Tigem managed to identify a specific pharmacological adjuvant capable of shielding the artificial enzyme and of enhancing its ability to reach the affected muscles. The trial results showed that in most of paediatric patients involved, combined therapy led to an increase in the activity of the replacement enzyme in the blood.

Preclinical development – Advanced stage

Stargardt Syndrome

Stargardt syndrome is a hereditary eye disease leading to gradual loss of eyesight. No treatments are available for this disease, which inevitably leads to blindness. Researchers at the Telethon Institute in Pozzuoli are developing a gene therapy to provide patients with a functioning version of the defective gene. This is a particularly challenging task, given the size of the gene. The initial results in an animal model are very encouraging, and could be transferred to human medicine in just a few years’ time.

Mucopolysaccharidosis type 3a

This metabolic disease is characterised by serious and rapid intellectual deterioration. No cure is available as yet, but researchers at Tigem in Pozzuoli are conducting laboratory work to devise a molecular therapy capable of restoring the missing protein in the nervous system.

Retinitis Pigmentosa

Retinitis pigmentosa  is a hereditary eye disease. It causes a gradual loss of eyesight. There is currently no treatment available that is capable of halting the disease, irrespective of age at onset and speed of progression. On the strength of the results achieved in previous studies concerned with Leber congenital amaurosis, researchers at Tigem have teamed up with American colleagues to work towards the application of gene therapy to this disease too, to correct the genetic defect at the root of the condition. One of the key challenges consists in developing gene transfer systems that are also suitable for large genes.

Usher Syndrome

Another form of retinitis pigmentosa is the autosomal recessive Usher syndrome (USH), the most common combination of genetic deafness and  blindness due to retinitis pigmentosa. Researchers at Tigem demonstrated that gene therapy based on dual AAV is safe and effective in animal models. A phase I/II, first-in-human, clinical trial of subretinal administration of dual AAV vectors will start in the next two years. It will be the first time the dual AAV vector approach is tested in humans.

Haemophilia

Haemophilia is one of the more common hereditary diseases. It manifests as a blood coagulation defect. The only treatment available at present is periodic administration of the missing coagulation factor. However, over time, the efficacy of the factor may diminish. Researchers at Tiget in Milan are developing a gene therapy solution, in vivo, that they hope will be a long-term and effective therapy. In this case, patients would receive a corrected version of the defective gene.

Preclinical development – Initial stage

Leber Congenital Amaurosis

This is a hereditary disease of the eye that results in severe vision loss, even in infants. There are currently no treatments capable of halting this disease, which leads to blindness within just a few years. In 2008, researchers at Tigem teamed up with American colleagues to conduct initial clinical gene therapy trials targeting one of the various forms of this disease. The results were promising both in terms of safety and of recovery of eyesight and eventually  led to regulatory approval of this therapy in US and EU in 2018.  Given these encouraging results, researchers are now working on applying the same strategy for other forms of this disease, for which a dozen genes are responsible. One of the key challenges consists in developing gene transfer systems that are also suitable for large genes.

Alpha-1 Antitrypsin Deficiency

This is among the most frequent genetic disorders and harms liver and lungs through different mechanisms: lack of functioning alpha-1 antitrypsin results in lung emphysema, while hepatic accumulation of mutant alpha-1 antitrypsin leads to progressive liver damage. Replacement therapy has recently been introduced to treat the lung disease, while no therapies are currently available for the liver disease and liver transplantation is the only option for most severe cases . Researchers at the Telethon Institute in Pozzuoli are investigating an innovative therapeutic approach to address liver disease, that is much less invasive than transplantation. The approach exploits the pharmacological stimulation of a specific gene (TFEB) to promote the disposal of the mutant alpha-1 antitrypsin that has accumulated in the hepatic cells. Researchers at Tigem’s leading-edge facility are screening an array of drugs, among those that have already been approved for clinical use, to find TFEB activating small molecules that can rapidly enter human clinical trials.  

Chronic Granulomatous Disease

This is a rare immunodeficiency disorder characterised by susceptibility to repeated fungal and bacterial infections. The only treatment available to date is bone marrow transplantation, which is not always possible. Researchers at Tiget in Milan are working to develop a gene therapy that is effective for the treatment of this disease, much in the manner already adopted for other immunodeficiency diseases such as the Wiskott-Aldrich syndrome.

Globoid Cell Leukodystrophy (Krabbe’s Disease)

This is a serious neurodegenerative disease occurring during infancy. At present, there are no treatments for this condition, which leads to a gradual loss of all cognitive and motor capacities already during the first years of life. Researchers at Tiget are trying to develop various therapeutic strategies, such as gene and cellular therapy, in order to provide these children with the missing enzyme.

Wilson’s Disease

This genetic disease is characterised by a toxic accumulation of copper in the organism. While this disease is currently controlled with drugs that can remove the excess copper, researchers at Tigem in Pozzuoli are looking into a better-targeted, effective alternative therapeutic approach.

Ipex

This is an extremely rare disease leading to marked disability and, in many cases, death – even in the first year of life. In these cases, the immune system attacks the patient’s own organs. The only therapies currently available are bone marrow transplantation (where a donor is available), or the use of immunosuppression drugs (alone or with steroids) to curb the immune system’s reaction. However, this therapy is not entirely effective. Targeted therapies might make it possible to prevent recurring infections and dermatitis.

Hereditary Deafness

Deafness is one of the most frequent sensorial defects. In Italy, about one child in a thousand is born deaf. In 60% of cases, the condition is of genetic origin. Opportunities for intervention vary according to conditions. In many cases, hearing aids and cochlear implants enable full or partial recovery of hearing.

Clinical development: our team

We employ a skilled Clinical development team in order to manage clinical studies.
The Head of Clinical Development  (HCD) is accountable for the end to end operational management of Telethon clinical studies and ensure that they all receive adequate support and resources and are executed in compliance with clinical trial governance and regulatory requirements. The team collaborates mainly with the two Telethon Institutes, SR-Tiget in Milan and Tigem in Pozzuoli (Naples), contributing to move projects from basic research to clinical research and taking care of all study management activities by coordinating dedicated local staff, such as the study and data manager, the clinical monitor and the regulatory officer, who conduct daily study activities.The table below reports the activities for each of the above mentioned figures. In addition, the HDC provides advice and consultancy on clinical trial design and set up to scientist and researchers whose projects are to approach the clinical phase.

Our key figures:

  • Head of Clinical Development: he is accountable for and in charge of coordinating all study activities. He guarantees personnel qualification, accuracy and continuity of activities.
  • Quality Assurance Manager (QM): he's quality assurance referee, independent supervision on clinical trial management ensuring adherence to GCP and legislation (Det. AIFA requirements).
  • Clinical Research Associate (CRA): he guarantees adherence to clinical protocol and GCP performing clinical monitoring visit (DM 2015_11_15). Monitoring of clinical studies.
  • Clinical Study Manager (CSM): he's reference person and responsible for the coordination of the trial clinical operation activities.
  • Regulatory Affair Officer (RAO): he deals with ethical and regulatory submission, preparation and review of study documents, TMF, interaction with Ethical Committee and Competent Authorities.
  • Data Manager (DM): he is responsible for creation of CRF, data entry, data management, data extraction.
  • Clinical Research Nurse (CRN): he is responsible for patient and biological sample management.

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