Scientific publications

Smart4fabry / Scientific publications

Impact of Chemical Composition on the Nanostructure and Biological Activity of α Galactosidase Loaded Nanovesicles for Fabry Disease Treatment

Fabry disease is a rare lysosomal storage disorder characterized by a deficiency of α-galactosidase A (GLA), a lysosomal hydrolase. The enzyme replacement therapy administering naked GLA shows several drawbacks including poor biodistribution, limited efficacy, and relatively high immunogenicity in Fabry patients. An attractive strategy to overcome these problems is the use of nanocarriers for encapsulating the enzyme. Nanoliposomes functionalized with RGD peptide have already emerged as a good platform to protect and deliver GLA to endothelial cells. However, low colloidal stability and limited enzyme entrapment efficiency could hinder the further pharmaceutical development and the clinical translation of these nanoformulations. Herein, the incorporation of the cationic miristalkonium chloride (MKC) surfactant to RGD nanovesicles is explored, comparing two different nanosystems-quatsomes and hybrid liposomes. In both systems, the positive surface charge introduced by MKC promotes electrostatic interactions between the enzyme and the nanovesicles, improving the loading capacity and colloidal stability. The presence of high MKC content in quatsomes practically abolishes GLA enzymatic activity, while low concentrations of the surfactant in hybrid liposomes stabilize the enzyme without compromising its activity. Moreover, hybrid liposomes show improved efficacy in cell cultures and a good in vitro/in vivo safety profile, ensuring their future preclinical and clinical development.

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Synthesis of Stable Cholesteryl−Polyethylene Glycol−Peptide Conjugates with Non-Disperse Polyethylene Glycol Lengths, published in ACS Omega 2020, 5, 5508−5519

A method for conjugating cholesterol to peptide ligands through non-disperse polyethylene glycol (ND-PEG) through a non-hydrolysable linkage is described. The iterative addition of tetraethylene glycol macrocyclic sulfate to cholesterol (Chol) renders a family of highly pure well-defined Chol-PEG compounds with different PEG lengths from 4 up to 20 ethylene oxide units, stably linked through an ether bond. The conjugation of these Chol-PEG compounds to the cyclic (RGDfK) peptide though Lys5 side chains generates different lengths of Chol-PEG-RGD conjugates that retain the oligomer purity of the precursors, as analysis by HRMS and NMR has shown. Other derivatives were synthesized with similar results, such as Chol-PEG-OCH3 and Chol-PEG conjugated to glutathione and Tf1 peptides through maleimide−thiol chemoselective ligation. This method allows the systematic synthesis of highly pure uniform stable Chol-PEGs, circumventing the use of activation groups on each elongation step and thus reducing the number of synthesis steps.

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Hospital Vall D´Hebron in collaboration with the H2020 funded Smart 4 Fabry project celebrated a seminar on Lisosomal Disorders, with a special focus on Fabry Disease.

Researchers and clinicians working in the field of lysosomal disorders had the opportunity to put in common the most recent advances in the diagnosis, pathophysiology and management of lysosomal storage disorders in general and of Fabry Disease in particular. During the seminar celebrated in Barcelona on November 19th, patients also had the chance to discuss with administrators and professionals about their expectations and demands, as well as their the need for collaborative actions aiming at designing plans for early diagnosis and easy access to the most suitable therapies.