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Posts Taged fabry-disease

Peptide functionalized nanoliposomes for biomolecule intracellular delivery, prepared using compressed CO2

The PhD Researcher Dolores Bueno researcher of NANOMOL Group and NANBIOSIS Unit 6 Biomaterial Processing and Nanostructuring Unit (from CIBER-BBN and ICMAB-SCIC) has defended her PhD thesis today, 20 March 2020, by videoconference from the ICMAB Meeting Room. No public was allowed due to the drastic measures of containment taken to tackle COVID-19.

Peptide functionalized nanoliposomes for biomolecule intracellular delivery, prepared using compressed CO

Abstract: Fabry disease is a rare disease caused by a gene mutation on the X-chromosome, which encodes α-galactosidase A (GLA) enzyme. The lack of GLA causes the accumulation of globotriaosylceramide at the lysosomes. The actual treatment is based in the enzyme replacement therapy (ERT), the intravenous administration of the enzyme. Nanotechnology is a powerful tool to develop enzyme-loaded nanosystems in order to ameliorate ERT efficacy.

DELOS-SUSP (Depressurization of an Expanded Organic Solution-Suspension) methodology enables the production of small unilamellar vesicles using compressed CO2. DELOS-SUSP allows the simultaneous encapsulation of different bioactives like RGD peptide and GLA in liposomes. This Thesis has used liposomes with RGD and GLA to generate a solid proof of concept for the treatment of Fabry disease.

Supervisor:

  • Nora Ventosa Rull, NANOMOL Group, ICMAB-CSIC Scientific Director of NANBIOSIS Unit 6
  • Elisabet González Mira, NANOMOL Group, ICMAB-CSIC

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Rare diseases Day February 29: combating Fabry Disease

29 of February is a ‘rare’ date and February, a month with a ‘rare’ number of days, has become a month to raise awareness about rare diseases and their impact on patients’ lives.  Since 2008 thousands of events happen every year all around the world and around the last day of February.

NanoMed Spain Platform and the Hospital of Sant Joan de Déu have organized the NanoRareDiseaseDay to present the latest innovations in the field of Nanomedicine for the treatment and diagnosis of rare diseases (diseases affecting less than 5 people per 10,000 inhabitants). Nora Ventosa, Scientific Director of NANBIOSIS U6 Biomaterial Processing and Nanostructuring Unit  (CIBER-BBN / ICMAB-CSIC) presented Smart4Fabry a European project with the aim of reducing the Fabry disease treatment cost and improve the life-quality of Fabry disease patients

Fabry disease is one of the rare diseases that currently lack a definitive cure. It is cause by lysosomal storage disorders (LSDs):  the deficiency of α-Galactosidase A (GLA) enzyme activity result in the cellular accumulation of neutral glycosphingolipids, leading to widespread vasculopathy with particular detriment to the kidneys, heart and central nervous system.

Smart-4-Fabry has been conceived to obtain a new nanoformulation of GLA, that will improve the efficacy and toleration compared to the actual treatment with non-formulated GLA. Four units of NANBIOSIS participate in the project:

U1 Protein Production Platform (PPP) led by Neus Ferrer and Antony Villaverde at IBB-UAB accomplish the production and purification in different expression systems for R&D purposes.

U3 Synthesis of Peptides Unit led by Miriam Royo at IQAC-CSIC performs all the chemical process of the Smart-4-Fabry  project, i.e. design and synthesis of peptides used as targeting ligands in the nanoliposome formulation

U6 Biomaterial Processing and Nanostructuring Unit led by Nora Ventosa and Jaume Veciana at ICMAB-CSIC undertakes tasks related to the manufacture of the nanoliposome formulation of GLA enzyme and the physico-chemical characterization (this unit counts with plants at different scales, from mL to L, which allow process development by QbD and process scale-up, as well as instrumental techniques for assessment of particle size distribution, particle concentration, particle morphology and stability, and Z-potential)

U20 In Vivo Experimental Platform led by Simó Schwartz and Ibane Abásolo at VHIR to carry out the non-GLP preclinical assays of the project (in vivo efficacy, biodistribution and tolerance/toxicity assays).

For further information about Fabry disease and the Smart4Fabry project: here

Nora Ventosa explaining the progress of the smart4fabry
project on nanoliposomes development for the treatment of Fabry disease
(Pictures by Nanomed Spain)
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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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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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Fabry disease awareness month, April

The Fabry International Network (FIN) association established the month of April as the “month of Fabry” to raise awareness and educate about this disease, a rare, progressive and with multi-organ involvement pathology.

Fabry Disease is one of several dozen Lysosomal Storage Disorders that interfere with the body’s ability to break down specific fatty substances. It is a rare disease and because the rate of occurrence is less than 1 in 200,000, it is considered as one of the many “Orphan” diseases. It is more common in women, but it occurs with greater severity in men.

Fabry disease is a metabolic disease that is produced by a deficiency of the ysosomal enzyme Alpha galactosidase. It is transmitted on the X chromosome. Fabry affected patients are missing alpha-galactosidase A (alpha-gal A) which results in sugars and fatty acids (Gb3) accumulating in the cells throughout the body and impairs the function of several major organs including the kidneys and heart. In 2001, enzyme replacement therapy appeared when the alpha-galactosidase protein (alpha- and beta-agalsidase) was synthesized in the laboratory using genetic engineering techniques. This treatment is injected into patients every 15 days to replenish the deficit levels of this enzyme and stop the progression of the disease.

CIBER-BBN, partner of NANBIOSIS, leads the European project Smart4fabry funded by the Horizon 2020 program, which will be developed through a consortium formed by 14 partners from 5 different countries. The CIBER-BBN coordinates the project through the participation of four of its groups that coordinate four units of NANBIOSIS (U1.Protein Production Platform (PPP), U3. Synthesis of Peptides Unit, U6. Biomaterial Processing and Nanostructuring Unit and U20. In Vivo Experimental Platform.) In addition, the consortium is formed by the University of Aarhus (Denmark), Technion Israel Institute of Technology (Israel), Joanneum Research (Austria), Biopraxis Research AIE (Spain), the spin off Nanomol Technologies SL (Spain) ), BioNanoNet (Austria), Drug Development and Regulation SL (Spain), the Covance Laboratories LTD group (UK), and Leanbio SL (Spain) Smart-4-Fabry has been conceived and developed to obtain a new nanoformulation of GLA, that will improve the efficacy and toleration of the treatment with non-formulated GLA. The final benefit will be seen as a considerable reduction on the Fabry disease treatment cost and a substantial improvement in the life-quality of Fabry disease patients.

Fabry International Network, FIN was established in 2005, as a non-for-profit organization registered in The Netherlands. The primary aim of the project is to facilitate collaboration between patient organizations around the world to support those affected by Fabry disease

FIN is connected to over 45 countries around the world. Membership is free and open to any National Patient Organization in which Fabry patients are represented. The National Fabry Disease Foundation – USA, for April 2018 Fabry Disease Awareness Month, have been providing an educational or information post on their Facebook page, every day of the month in April. The NFDF also distributed their My Health Handbook kit  and, so far, distributed about 700 kits to individuals with Fabry disease. Fabry Australia have a new website and they are also running a new social media campaign. Fabry Support & Informatie Groep Nederland, FSIGN, since 2005  has organized every first Saturday of April (in the Fabry Awareness Month April) to be the Fabry women’s day. Japan Fabry Disease Patients and Family Association, in awareness month JFA held an open seminar at Fukuoka University Medical hall with lectures on three major topics: Newborn Mass Screening, Current Treatments and Employment and Clinical Genomics. In Spain the Fabry patient organization are the Spanish Fabry MPS Association

 

The Fabry International Network will cellebrate the 6th Fabry Expert Meeting on
8th – 10th June 2018 at the Vilnius Grand Resort, Ežeraičių g. 2, Ežeraičių km., Avižienių sen., Vilniaus raj., LT-14200, Lietuva.

DRAFT Full Program

 

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Extraordinary doctoral award

Ingrid Cabrera, member of the NANOMOL group that coordinates Unit 6 of NANBIOSIS, has obtained the extraordinary doctoral award from the Universitat Autònoma de Barcelona for her thesis “Nanovesicle-bioactive conjugates to be used as nanomedicines, prepared by a one-step scalable method Using CO₂-expanded solvents“.

This thesis was directed by Jaume Veciana, Scientific Director of NANBIOSIS and Nora Ventosa, Scientific Director of Unit 6 of NANBIOSIS.

The main objectives of the  PhD Thesis of Dr. Ingrid Cabrera were the preparation and study of multifunctional nanovesicle based nanoformulation of alfa-galactosidase for the treatment of Fabry desease as well as of another multifunctional nanovesicle based nanoformulation of epidermal growth factor for the treatment of complex wounds. Both nanoformulations were prepared by a one-step procedure using compressed fluids at U6 of Nanbiosis. This platform also provided many nanoparticles characterization facilities that enabled to obtain important information on the supramolecular organization and characteristics of the produced multifunctional nanovesicles that were key for understanding their biological activities.

Extraordinary doctoral award
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Unit 1 of NANBIOSIS, Protein Production Platform (PPP), Unit 3, Synthesis of Peptides, Unit 20, In Vivo Experimental Platform and Unit 6, Biomaterial Processing and Nanostructuring Unit, have jointly developed the research conducted in relation with a CO2-based methodology for the one-step production of protein-nanoliposome conjugates as bio-active nanomaterials with therapeutic interest. The results have been published in Advanced Healthcare Materials: http://www.ncbi.nlm.nih.gov/pubmed/26890358

Unit 1 of NANBIOSIS, Protein Production Platform (PPP), Unit 3, Synthesis of Peptides, Unit 20, In Vivo Experimental Platform and Unit 6, Biomaterial Processing and Nanostructuring Unit, have jointly developed the research conducted in relation with a CO2-based methodology for the one-step production of protein-nanoliposome conjugates as bio-active nanomaterials with therapeutic interest. The results have been published in Advanced Healthcare Materials: http://www.ncbi.nlm.nih.gov/pubmed/26890358

“a-Galactosidase A Loaded Nanoliposomes with Enhanced Enzymatic Activity and Intracellular Penetration I. Cabrera, I. Abasolo, J. L. Corchero, E. Elizondo,  P. Rivera, E. Moreno, J. Faraudo, S. Sala, D. Bueno, E. González-Mira, M. Rivas, M. Melgarejo, D. Pulido, F. Albericio, M. Royo, A. Villaverde, M. F. García-Parajo, S. Schwartz Jr., N. Ventosa,*, and J. Veciana,*

Lysosomal storage disorders (LSD) are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of macromolecules such as lipids, glycoproteins and mucopolysaccharides. For instance, the lack of alpha-Galactosidase A (GLA) activity in Fabry disease patients causes the accumulation of glycosphingolipids in the vasculature leading to multiple organ pathology.

Enzyme replacement therapy (ERT), which is the most common treatment of LSD, exhibits several drawbacks mainly related to the instability and low efficacy of the exogenously administered therapeutic enzyme. In this work, the unprecedented increased enzymatic activity and intracellular penetration achieved by the association of a human recombinant GLA to nanoliposomes functionalized with RGD peptides is reported. Moreover, these new GLA loaded nanoliposomes lead to a higher efficacy in the reduction of the GLA substrate named globotriasylceramide (Gb3) in a cellular model of Fabry disease, than that achieved by the same concentration of the free enzyme. The preparation of these new liposomal formulations by DELOS-SUSP, based on the Depressurization of a CO2-Expanded Liquid Organic Solution, shows the great potential of this CO2-based methodology for the one-step production of protein-nanoliposome conjugates as bioactive nanomaterials with therapeutic interest.

“a-Galactosidase A Loaded Nanoliposomes with Enhanced Enzymatic Activity and Intracellular Penetration”
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