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A more effective nanomedicine has been developed for the treatment of Fabry rare disease.

28 February: International Rare Disease Day

  • This is one of the major achievements of the European Smart4Fabry project, which is now coming to an end after four years of work.
  • The results have been made possible by nanotechnology and the approach developed could be applied to other drugs in the future.
  • The new drug improves on current treatments and helps reduce costs and improve patients’ quality of life.

Barcelona, 26 February 2021.- The advance of nanomedicine opens up new possibilities in the development of drugs, such as the one recently developed for the rare disease Fabry, with improved efficacy compared to existing authorised treatments.

Thus, the European Smart4Fabry project has come to an end with one of the best results possible: the designation of a new orphan drug by the European Commission and the possibility of making progress in the treatment of Fabry, a rare disease that is estimated to affect approximately 2.6 out of every 10,000 people in the EU.

It is a chronic debilitating disease due to recurrent episodes of severe pain that is difficult to control with conventional analgesics, and it is life-threatening due to renal failure and associated cardiovascular and cerebrovascular complications.

“With this designation we have made a major achievement, not only for Fabry patients, but also for other pathologies that can benefit from this same approach, made possible by nanotechnology,” explained Nora Ventosa, Scientific Director of NANBIOSIS Unit 6 Biomaterial Processing and Nanostructuring Unit of CIBER-BBN and ICMAB-CSIC who coordinated the project.

Need for new treatments for the disease

This disease, also known as Anderson-Fabry disease, represents the most common lysosomal storage disorder. It is caused by an absence or deficiency of the enzyme α-galactosidase A (GLA), which results in the lysosomal accumulation of globotriaosylceramide (Gb3) and its derivatives in the lysosomes of a wide variety of tissues, responsible for the clinical manifestations. Current treatments consist of intravenous administration of the GLA enzyme, but have limited efficacy and poor biodistribution.

The drug that has been developed is a new nanoformulation of GLA (nanoGLA) that improves efficacy compared to the reference treatment with non-nanoformulated GLA. “The third-generation liposomal product we have developed in the project has demonstrated, at preclinical level, improved efficacy, compared to authorised enzyme replacement treatments, demonstrating that the strategy of supplying the affected cells with the GLA enzyme via the smart nanoliposome is highly successful”, explained Ibane Abasolo, Scientific Coordinator of NANBIOSIS U20 of CIBER-BBN and VHIR, who is responsible for the efficacy studies in the project.

The nanoGLA product was obtained using DELOSTM formulation technology, an innovative platform for the robust production of nanomedicines in an efficient and sustainable manner.

The Committee for Orphan Medicinal Products, the European Medicines Agency’s (EMA) committee responsible for recommending orphan designation of medicines for rare diseases, has considered these results to have a clinically relevant advantage over current enzyme replacement therapies.

The designation of orphan drug, in addition to recognising the significant benefit of the new nanomedicine over products already licensed for Fabry disease, has important implications for the translation of the new therapeutic product from bench to bedside.

Those responsible for these results, including several CIBER-BBN groups, highlight that the new formulation helps to improve treatments, reduce costs, and improve the quality of life of Fabry patients.

Interdisciplinarity and public-private collaboration

The Smart4Fabry project has been running since 2017 thanks to European funding of €5.8 million, from the Horizon 2020 programme. This was possible thanks to the collaboration of several CIBER-BBN groups and NANBIOSIS Units at the Institute of Materials Science of Barcelona (ICMAB-CSIC) with the abouve mentioned NANBIOSIS Unit 6, the Institute for Advanced Chemistry of Catalonia (IQAC-CSIC) with NANBIOSIS Unit 3 of
Synthesis of Peptides Unit, led by Miriam Royo, the Vall d’Hebron Research Institute (VHIR) with NANBIOSIS Unit 20 and the Institute of Biotechnology and Biomedicine of the Autonomous University of Barcelona (IBB-UAB) with NANBIOSIS Unit 1 Protein Production Platform (PPP), whose work in this project was led by José Luis Corchero. It has also been necessary to contribute knowledge from different academic and business disciplines.

The project consortium also includes public institutions such as the University of Aarhus (Denmark), Technion Israel Institute of Technology (Israel) and Joanneum Research (Austria); and the companies Biokeralty (Spain); Nanomol Technologies SL (Spain); BioNanoNet (Austria), Drug Development and Regulation SL (Spain), the Covance Laboratories LTD group (UK) and Leanbio SL (Spain), which have provided the necessary expertise in nanotechnology and biotechnology, physicochemical characterisation, in vitro and in vivo biological evaluation, formulation and grading of nanomedicines, and pharmaceutical development and production under the guidelines of regulatory agencies.

CIBER and CSIC, promoters of orphan drugs

Orphan Drug Designations (ODDs) seeks to facilitate the arrival of treatments for rare diseases on the market. Several incentives are associated with ODDs, such as market exclusivity, fee reductions and specific scientific advice.

To date, CIBER has promoted eleven orphan drugs designated by the EMA, mainly from the thematic area of Rare Diseases (CIBERER), this being the first from CIBER-BBN.

On the other hand, this is the fourth ODD that the CSIC has obtained, and the first time it refers to a nanoformulated drug.

Orphan drug designation by the European Medicines Agency has several advantages, such as receiving a commercialisation authorisation for 10 years during which similar products cannot be commercialised, the availability of free or low-cost scientific advice and support protocols, and exemption from designation fees. In addition, entities developing orphan drugs have access to specific grants from the European Union and member states’ programmes.

More information

Scientific Culture Unit UCC+i CIBER cultura.cientifica@ciberisciii.es

Other related news

Smart-4-Fabry final workshop
Rare diseases Day February 29: combating Fabry Disease
Fabry disease & Smart4Fabry project
Lysosomal Rare Disorders: Focus on Fabry Disease
Fabry disease awareness month, April
“a-Galactosidase A Loaded Nanoliposomes with Enhanced Enzymatic Activity and Intracellular Penetration”

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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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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 CO2 

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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#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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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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“Smart-4-Fabry”: European project focused on the Fabry rare disease, participated by 4 units of NANBIOSIS

  • Smart-4-Fabry is a project coordinated by CIBER-BBN, funded by the European Commission within the Horizon 2020 Research and Innovation program with € 5.8 M for 4 years, which aims to develop a new nanomedicine for the treatment of the Fabry rare disease.

 

  • Fabry disease is a rare disease belonging to the group of lysosomal storage disorders, with a global incidence of 1:5,000 – 1:10,000, representing a priority health problem at European level.

 

The European project “Smart-4-Fabry”, is coordinated by CIBER-BBN, specifically by NANOMOL group at ICMAB-CSIC (Dr. Nora Ventosa) and the Biomaterial Processing and Nanostructuring Unit (U6) of  ICTS “NANBIOSIS”, and it also counts with the participation of NANBIOSIS Units U1 Protein Production Platform (PPP), U3 Synthesis of Peptides Unit, and U20 In vivo Experimental Platform.

Fabry disease is an inherited genetic disorder of the lysosomal storage group, which affects many organs and parts of the body, as it is caused by the accumulation of a lipid in the lysosomes of the cells, altering their functions and leading to cell death. This accumulation is due to the lack of an enzyme, α-Galactosidase A (GLA). The symptoms are many: limb pains, stains on the skin, problems with sweating, blurred frontal vision, gastrointestinal problems, loss of hearing, etc. In the long term it can cause renal failure, and heart and central nervous system problems.

Patients can lead a normal life with the current treatment called “enzyme replacement therapy”, where GLA is administered intravenously to patients. However, this treatment exhibits several drawbacks, related to a high instability, high immunogenicity or low efficacy of this molecule crossing cell walls. The development of a new treatment for this disease, as well as for other rare diseases, has become a priority challenge within the European program H2020.

Smart-4-Fabry, acronym for “Smart functional GLA-nanoformulation for Fabry disease”, was born with the idea of ​​obtaining a new nanoformulation of GLA that will improve the efficacy and tolerance of the existing treatments. The project will advance from experimental proof of concept, to the preclinical regulatory phase. The ultimate goal is to reduce the treatment cost and to improve the quality of life of patients with Fabry disease.

Smart-4-Fabry, involves the participation of fourteen partners from five different countries from academia and industry. The consortium is formed by: Network of Biomedical Research Centers: Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) with the NANOMOL group at the Institute of Materials Science of Barcelona (ICMAB-CSIC), the Drug Delivery and Targeting Group at the Vall d’Hebron Research Institute (GDLF-VHIR), the Peptide Synthesis Unit at the Barcelona Science Park (UQC-PCB), and the Biotechnology and Biomedicine Institute of the Autonomous University of Barcelona (IBB-UAB) (Spain); Aarhus University (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 (UK) group; and Leanbio SL (Spain).

For further information: http://smart4fabry.eu/

 

 

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