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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - Smart-4-Fabry (Smart multifunctional GLA-nanoformulation for Fabry disease)

Teaser

Summary

\"Lysosomal storage disorders (LSDs), such as Fabry, Gaucher, Hunter, and Sanfilippo diseases are a group of rare diseases that currently lack a definitive cure. LSDs individually occur with incidences of less than 1:100,000; but as a group, the incidence is about 1:5,000 - 1:10,000, representing a serious global health problem. Therefore, development of new treatments for this type of rare diseases has become a key priority for European Research policy.

For instance, the lack of Î±-galactosidase A (GLA) activity in Fabry disease (FD) patients causes the accumulation of glycosphingolipids (such as Gb3) in the vasculature leading to multiple organ pathology, and the death of patients before 45 years old. Enzyme replacement therapy (ERT), which is the most common treatment of LSDs, exhibits several drawbacks: short plasma half-life (high uptake of the GLA by the liver and high degradation rate), poor biodistribution, high immunogenicity, and low capability to cross biological barriers such as the blood brain barrier (BBB). In this scenario, a correct nanoformulation of the GLA enzyme is foreseen as a critical step to improve the ERT.

In the frame of Smart-4-Fabry EU project (#720942), a new GLA nanoformulation (nano-GLA) more effective than current treatments for FD patients will be obtained. Such gain in the efficacy would further allow lowering the clinical dose and spacing the administration schedule for FD patients (currently being administered every other week). The final benefit will be seen as considerable reduction on the FD treatment cost and a substantial improvement in the quality of life for FD patients.

The Smart-4-Fabry project is expecting to last for 48 months and contemplates the necessary activities to advance the innovative nano-GLA from the current experimental Proof of Concept (TRL3) to preclinical regulatory phase (TRL5-6). A one-step method based on the use of green CO2 will be used for the manufacturing of this novel nanoformulation under GMPs. The final GLA nanoformulation will have tailored transport of GLA through cell membranes and BBB.

Several research groups with experience in nanomedicine and molecular self-assembling (CIBER-BBN/Spain, Aarhus University/Denmark, Technion/Israel- and Joanneum Research/Austria), together with a recognized SME in the field of pre-clinical testing (Covance Laboratories/UK), a nanomedicine industrial manufacturer (Biopraxis/Spain), a company specialized on industrial implementation of CO2-based nanomedicine manufacturing platforms (Nanomol Technologies/ Spain), a recognized CRO in developmental processes of biological products, experts on industrial safety (BioNanoNet/ Austria) and drug regulation (DDR/ Spain), are joining efforts to bring the new nanomedicine for Fabry disease treatment to the doors of the clinical testing (Phase I).
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Work performed

The work performed by the Smart-4-Fabry consortium partners from the beginning of the project to the end of the period covered by the report (first 18 months) has permitted to:

- Achieve quality control over the self-assembly of nano-GLA molecular components and its physicochemical parameters, which have allowed to define preliminary critical quality attributes (CQA) and specifications for the GLA nanoformulation;
- Develop a novel GLA enzyme by a stable expression â€“based production method to perform the optimization of the nanoformulation towards the obtainment of the final GLA-nanoformulation. This GLA contains tags, hereafter GLAcmycHis, and it is an intermediate GLA version just for R&D purposes;
- Start the development of the stable cell clone from a freedom-to-operate cell line to manufacture GLA tag free (final GLA version for the preparation of nano-GLA batches for the future preclinical studies, including the toxicology testing);
- Define the quasi final nano-GLA prototype since it still contains the intermediate GLA version (GLAcmycHis), with well-established membrane components, to start the scale-up activities and setting-up methodologies for preclinical studies;
- Elaborate a Briefing Document to request a Briefing Meeting with the Innovation Task force (ITF)-EMA to obtain regulatory authority feed-back, in order to be the final nano-GLA in compliance with the requirements of the pharmaceutical industry and regulatory authorities;
- Start the design and implementation of a pre-GMP pilot plant for the of the quantities of nano-GLA needed for regulatory preclinical trials;
- Create an exploitation plan and a Canvas Business Model in order to ensure at the end of the project the translation of the project results to patients suffering from FD.

Final results

Smart-4-Fabry should end up with a completed regulatory safety and toxicology package supporting future nano-GLA clinical development in FD. With the achievement of this objective, the project aims to strategically contribute to the adoption of Key Enabling Technologies (KETs), such as nanotechnology, industrial biotechnology and advanced materials in Europe, through the demonstration of the capacity to get more efficient, greener and safer therapies.

Smart-4-Fabry will have a wide impact on improving the industry competitiveness at two levels: it will have a direct impact on the companies, allowing the generation of a new, highly competitive product that will, additionally, open new markets. Indeed, the project success will open a pathway for tailored solutions to other LSD and other pathologies.

Fulfilment of Smart-4-Fabry will impact on a major health problem, the existence of new therapies for rare diseases, which constitutes a priority societal challenge as shown in the H2020 Work Programmes. Another important impact is related to its contribution to support the European Strategy for KETs, which aims to reverse the decline in manufacturing as this will stimulate growth and jobs.