Telethon Foundation funds ICGEB research on rare genetic diseases

Two ICGEB research projects on rare genetic diseases have been funded under the 2020 Telethon Foundation call – giving hope for concrete responses to patients.

World Rare Disease Day falls on 28 February, and we are delighted to announce that two of the projects submitted by ICGEB’s research groups working in this area have been funded by Telethon. Federica Benvenuti who heads the Cellular Immunology lab, and Andrés Muro, head of the Mouse Molecular Genetics lab and their teams work respectively, on Wiskott-Aldrich syndrome and Fabry disease.

Wiskott-Aldrich syndrome affects 1 in every million boys born and it is a severe immune deficiency complicated by autoimmunity. The current curative options include bone marrow transplantation of matched donors or gene-corrected stem cells. One of the long-lasting complications of the disease is represented by autoimmune manifestations that are often treated by non-specific immunosuppressive medicaments that collide with immune deficiency. There is, therefore, urgent to identify the origin of autoimmunity to tailor personalised intervention.

“Our preliminary data show that excessive inflammation and WAS autoimmunity may arise from erroneous recognition of endogenous DNA contained within our body’s cells as an enemy. The central system that recognises and initiates immune responses against endogenous DNA is called cGAS-STING.” Comments Dr. Benvenuti. “In this project, we aim to understand the reasons for the malfunctioning of cGAS-STING in WAS mutant cells and to explore ways to correct it. In addition, we aim to analyse novel parameters to score patients based on the presence of inflammatory profiles in their blood cells in order to personalise curative options.”

The other three-year project funded focuses on Fabry disease (FD), which is a rare X-linked lysosomal storage disorder caused by mutations in the alphagalactosidase A (GLA) gene. First symptoms may appear in childhood or adolescence (as early as 2 years of age), with a systemic accumulation of glycosphingolipids in lysosomes, progressive multi-organ failure, and eventually, death. The only specific treatment consists in the administration of a recombinant enzyme (produced in a laboratory), a procedure called Enzyme Replacement Therapy (ERT).

“This therapy”, explains Andrés Muro, “has several limitations, such as the development of antibodies against the recombinant enzyme affecting efficacy, and high costs,” and continues: “We will permanently modify the genome of hepatocytes, in such a manner that the GLA enzyme will be produced at very high levels and secreted into the bloodstream, converting the liver into a bio-factory. The target organs will then capture the circulating enzyme, as occurs with ERT.”

“Our preliminary data is very encouraging and we expect the approach will be effective and could be potentially translated to the clinic, also to juvenile patients, with a substantial reduction in the costs, and increased safety and efficacy of treatment.”

The Telethon Foundation has selected to support 45 projects for more than 40 genetic diseases.


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