February 28 is Rare Disease Day. The Vall d'Hebron Research Institute (VHIR) is investigating to learn more about multiple rare diseases, among which is Fabry disease, a hereditary lysosomal metabolic disease that affects 1 in 7,700 people. The CIBBIM-Nanomedicine-Drug Delivery and Targeting group has been working for ten years on different strategies to improve the treatment of Fabry patients. In this sense, a study jointly led by the CIBBIM-Nanomedicine, Drug Delivery and Targeting group and the Institute of Materials Science of Barcelona (ICMAB-CSIC) has shown that carrying the therapeutic enzyme through liposomes could be a promising strategy to improve the treatment of Fabry disease. The results have been published in the journal https://pubs.acs.org/doi/10.1021/acsami.0c16871 ACS Applied Materials & Interfaces and are part of the European https://smart4fabry.eu/ Smart4Fabry project led by the Bioengineering, Biomaterials and Nanomedicine CIBER (CIBER-BBN).Fabry disease is caused by mutations in the protein alpha-galactosidase A (GLA), an enzyme found in the lysosomes of cells that is responsible for metabolizing some substrates such as globotriaosylceramide (Gb3). The lack of this enzyme leads to an accumulation of these substrates in cells, especially in the endothelial cells of blood vessels. It is a debilitating chronic disease due to recurrent episodes of severe pain that are difficult to control with conventional analgesics, and potentially fatal due to kidney failure and the associated cardiovascular and cerebrovascular complications.The usual treatment for Fabry patients is GLA enzyme replacement therapy. However, the administration of this enzyme into the bloodstream is not enough to reverse the disease, especially in advanced stages. This is because the half-life of the protein in the blood is very short and it is not able to reach all the target organs. To protect the GLA that is administered, strategies based on nanotechnology have been designed that consist of introducing the GLA protein into nanoparticles. The advantages and disadvantages of the different nanoparticulate systems for this type of disease are described in a review recently published by the VHIR Drug Delivery and Targeting group in the journal https://onlinelibrary.wiley.com/doi/abs/10.1002/wnan.1684 WIREs Nanomedicine and Nanobiotechnology.In this new work, the researchers have worked to improve the stability and protein-loading capacity of nanoparticulate systems that act as vehicles for GLA. They have found that the effectiveness of these lipid nanoparticles improves when they are accompanied by a surfactant called miristalkonium chloride (MKC). Specifically, the study explored two types of nanometric systems: non-liposomal ones called quatsomes, and others called hybrid liposomes. This surfactant was incorporated in both systems, which promotes the enzyme's interaction with the vehicle components and favours its stability.When comparing the results with both particles, it was found that the quatsomes completely suppressed the activity of GLA, so they would not be a good strategy. However, "the hybrid liposomes increased both the ability to transport the GLA enzyme and its activity, generating a more efficient system, capable of reducing more Gb3 than the treatment currently given to Fabry patients", explains Dr. Ibane Abasolo, principal investigator of the CIBBIM-Nanomedicine group, Drug Delivery and Targeting group of VHIR and researcher at CIBER-BBN. When tested in mice, good tolerance was demonstrated and no side effects developed. Thus, this system was shown to have significant benefits over the usual enzyme replacement therapy with free GLA. "These results allow us to approach the clinic and carry out pre-clinical regulatory studies", reflects Dr. Abasolo.The study, along with others that have not yet been published, has led to the Orphan Drug Designation for this type of liposomes, which provides incentives to stimulate research and development of new drugs. The Committee for Orphan Medicinal Products (COMP) has considered these results to constitute a clinically relevant advantage over current enzyme replacement therapies. The orphan drug designation, in addition to being a recognition of the significant benefit that the new nanomedicine offers compared to products already authorized for Fabry disease, has important implications in the transfer and translation of the new therapeutic product to more advanced phases of developing. "With this designation we have reached a great achievement, not only for Fabry patients, but also for other pathologies that can benefit from this same approach, made possible thanks to nanotechnology", explains Nora Ventosa, researcher at CIBER-BBN and ICMAB -CSIC that has coordinated the Smart4Fabry project.The researchers responsible for these results point out that the new formulation helps to improve treatments, to reduce costs and to improve the quality of life of Fabry patients. Furthermore, the liposome technology is already licensed to one company (Biokeralty) and a screening patent has recently been applied for its use in enzyme replacement therapy.Interdisciplinarity and public-private collaborationThe Smart4Fabry project has been developing since 2017 thanks to European funding - from the Horizon 2020 program - of 5.8 million euros. Its achievement has been possible thanks to the collaboration of several groups of the CIBER-BBN in the Institute of Materials Science of Barcelona (ICMAB-CSIC), the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), both of the CSIC, the Vall d'Hebron Research Institute (VHIR) and the Institute of Biotechnology and Biomedicine of the Autonomous University of Barcelona (IBB-UAB). The contribution of knowledge from different disciplines from both the academic and business fields has also been necessary.The project consortium is also made up of public institutions such as the University of Aarhus (Denmark), Technion Israel Institute of Technology (Israel) and Joanneum Research (Austria), and the Biokeralty companies (Spain), Nanomol Technologies SL (Spain), BioNanoNet (Austria), Drug Development and Regulation SL (Spain), the group Covance Laboratories LTD (UK) and Leanbio SL (Spain), which have provided the necessary experience in nanotechnology and biotechnology, physicochemical characterization, in vitro and in vivo biological evaluation , formulation and scaling of nanomedicines and pharmaceutical development and production under the guidelines of regulatory agencies.