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Posts Taged lysosomal-rare-disorders

Smart-4-Fabry final workshop

Next Wedneday, February 3, 2021 will take place the on-line event Smart-4-Fabry Final Workshop.  

Smart-4-Fabry is a european project, coordinated by CIBER-BBN wich has been developed during four years. This project is a sign of cooperation at European level to boost nanomedicine development and translation to clinical stages.

This project is also a clear example of the relevance of access to advanced research infrastructures as NANBIOSIS -ICTS. Four NANBIOSIS units have collaborated and contributed to Smart-4-Fabry development:

“The Fabry disease (FD) is a lysosomal storage disorder (LSD) that currently lacks an effective treatment” as Prof. Nora Ventosa, IP of the project, explained for NANBIOSIS blog – The aim of Smart-4-Fabry is to obtain a new nanoformulation of GLA, that will improve the efficacy and toleration compared to the actual treatment with non-formulated GLA.

In the final workshop experts will talk about how, why and for what the solution proposed by Smart4Fabry was conceived.

Registrations and program at https://smart4fabry.cientifis.com/

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Fabry disease & Smart4Fabry project

The Fabry disease (FD) is a lysosomal storage disorder (LSD) that currently lacks an effective treatment. Lysosomes are spherical vesicles, which contain hydrolytic enzymes found in nearly all animal cells. LSDs are caused by lysosomal dysfunctions, usually because of the deficiency of a single enzyme required for the metabolism of macromolecules such as lipids, glycoproteins and mucopolysaccharides. Fabry disease is a progressive, X-linked inherited disorder caused by deficiency or absence of the α-galactosidase A (GLA) activity, an enzyme involved in the glycosphingolipid metabolism. The substrates of GLA are glycosphingolipids, being the primary substrate the globotriaosylceramide (Gb3). Therefore, the failure of GLA activity leads to progressive intracellular accumulation of Gb3, in many cells, particularly in renal epithelial cells, endothelial cells, pericytes, vascular smooth muscle cells, cardiomyocytes, and neurons of the autonomic nervous system, leading to multisystemic clinical symptoms. First clinical signs of FD occur during childhood and, over time, microvascular lesions of the affected organs progress leading to early death. It affects mostly men but serious cases have also been reported in women.

There are currently three products authorized in the EU for the treatment of FD. Two products available in EU since 2001 for Enzymatic Replacement Therapy (ERT), Replagal (Shire Human Genetic Therapies AB) and Fabrazyme (Genzyme Europe B.V.), which have to be i.v. administered every other week. The ERT strategy is based on supplying recombinant GLA to cells, reversing several of the metabolic and pathologic abnormalities. There is a third product in the EU market since 2016, which is based on the chaperone migalastat hydrochloride (Galafold Amicus Therapeutics UK Ltd), designed to selectively and reversibly bind with high affinity to the active sites of certain mutant forms of GLA, facilitating proper protein folding and allowing for correct trafficking of the mutant enzyme. However, it is a genotype-specific treatment (only one-third to one-half of mutations may be amenable).

To date, no direct comparisons exist between Fabrazyme and Replagal but significant clinical benefits compared with placebo, however, have been demonstrated with ERT, with positive effects on the heart, kidneys, nervous system and quality of life. Of note, a stabilization of renal function was only observed at an early phase of FD.

ERT success with free GLA is limited mainly due to the instability and low efficacy of the exogenously administered therapeutic enzyme. Furthermore, some patients can develop immune responses after receiving the infused recombinant enzyme. Clinical data has confirmed that the immunological consequences of ERT may impair efficacy in some patients. Furthermore, the short elimination t1/2 of the enzyme and the need for repeated administration of large amounts of enzyme are other limitations of current ERT. In addition, GLA does not cross of the Blood Brain Barrier (BBB), which prevents the product for reducing the Gb3 deposits in the central nervous system (CNS). Moreover, it is a lifelong treatment which becomes a burden for the health system due to its extremely high cost.

Therefore, there is a need for other therapeutic strategies, which can either serve as primary or supplemental treatments. Gene and substrate reduction therapies constitute alternative therapies which are at present under investigation.

The European “Smart-4-Fabry” project aims to develop a new nanoformulation based on the encapsulation of the GLA enzyme in nanoliposomes, to improve the current ERT of FD. A Consortium formed by ten partners, including private companies and public institutions in Europe and Israel, has been granted (July 2017) with a Horizon2020 financial programme by the European Commission (H2020-NMBP-2016-2017; call for nanotechnologies, advanced materials, biotechnology and production; Proposal number: 720942-2).

The project is expecting to last for 48 months and contemplates the necessary activities to advance a nanoliposome formulation of GLA enzyme, i.e., nano-GLA, from an experimental proof of concept up to an advanced nonclinical stage of development. The S4F should complete an advanced regulatory safety and toxicology package supporting future nano-GLA clinical development in patients with FD.

To the best of S4F knowledge, there is no previous experience on the encapsulation of a GLA for treating FD patients following an ERT approach.

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#RareDiseaseDay: Fabry lysosomal disease

Rare Disease Day is annually held on the last day of February in more than 100 countries with the main objective of raising awareness about rare diseases and their impact on the life of patients to the general public and in particular to policy makers, public authorities, industry representatives, researchers and professionals. Rare diseases are those that affect less than 1 in 2000 people. There are more than 300 million people living with one or more than more than 6000 rare diseases worldwide identified.

Among the events organized we wont to mention the Nano Rare Diseases Day held in Barcelona on February 27, organized by the Hospital de Sant Joan de Déu and the NanoMed Spain Platform, where the latest innovations in the field of Nanomedicine for the treatment and diagnosis of these diseases will be announced, with themes ranging from early diagnosis, controlled release of drugs or the development of new therapies. During this day, experts in Nanomedicine from different fields – research, business, clinical practice, health authorities, patients, etc. – will present the latest advances and give us the opportunity to discover the progress generator that Nanomedicine means for health as creator of new opportunities in the diagnosis and treatment of minority diseases.

Nora Ventosa, Scientific Director of NANBIOSIS U6 Biomaterial Processing and Nanostructuring Unit (CIBERBBN-ICMAB_CSIC) will explain the European Smart-4-Fabry Project: use of nanotechnology for the development of a new drug for the treatment of Fabry lysosomal disease  where four units of NANBIOSIS colaborate.

Inscriptions

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Lysosomal Rare Disorders: Focus on Fabry Disease

Last November 19, Vall d’Hebron held a seminar  on Lysosomal Rare Disorders: Focus on Fabry Disease as  part of the Rare Diseases Program at the Vall d’Hebron Campus, in collaboration with the European Commission, the Center for Biomedical Research Network on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) and the CIBBIM-Nanomedicine at Vall d Hebron Research Institute (VHIR) through the Smart-4-Fabry projec

In the  second plenary session, moderated by Nora Ventosa and Simó Schwartz, Scientific Directors of NANBIOSIS units 6 and 20 and devoted to New therapeutic strategies for lysosomal disorders, the speakers presented their findings regarding biomarkers, genetic variants and treatment protocols. Ibane Abasolo, Scientific Coordinator of NANBIOSIS Unit 20 gave a talk on Nanomedicine in lysosomal disorders. Project Smart4Fabry .

The Smart4Fabry project, coordinated by CIBER-BBN and with the participation of NANBIOSIS units U3 Synthesis of Peptides Unit, U6 Biomaterial Processing and Nanostructuring Unit and U20 Functional Validation & Preclinical Research (FVPR), was described in the course of this specific day on lysosomal diseases and Fabry’s disease.

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