Advancing rare disease treatment: EMA's decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation.

Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency's Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.

The European landscape for gene therapies in orphan diseases: 6-year experience with the EMA Committee for Orphan Medicinal Products.

In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.

Nanoparticle- and Microparticle-Based Vaccines against Orbiviruses of Veterinary Importance.

Bluetongue virus (BTV) and African horse sickness virus (AHSV) are widespread arboviruses that cause important economic losses in the livestock and equine industries, respectively. In addition to these, another arthropod-transmitted orbivirus known as epizootic hemorrhagic disease virus (EHDV) entails a major threat as there is a conducive landscape that nurtures its emergence in non-endemic countries. To date, only vaccinations with live attenuated or inactivated vaccines permit the control of these three viral diseases, although important drawbacks, e.g., low safety profile and effectiveness, and lack of DIVA (differentiation of infected from vaccinated animals) properties, constrain their usage as prophylactic measures. Moreover, a substantial number of serotypes of BTV, AHSV and EHDV have been described, with poor induction of cross-protective immune responses among serotypes. In the context of next-generation vaccine development, antigen delivery systems based on nano- or microparticles have gathered significant attention during the last few decades. A diversity of technologies, such as virus-like particles or self-assembled protein complexes, have been implemented for vaccine design against these viruses. In this work, we offer a comprehensive review of the nano- and microparticulated vaccine candidates against these three relevant orbiviruses. Additionally, we also review an innovative technology for antigen delivery based on the avian reovirus nonstructural protein muNS and we explore the prospective functionality of the nonstructural protein NS1 nanotubules as a BTV-based delivery platform.

3D Printing: An Emerging Technology for Biocatalyst Immobilization.

Employment of enzymes as biocatalysts offers immense benefits across diverse sectors in the context of green chemistry, biodegradability, and sustainability. When compared to free enzymes in solution, enzyme immobilization proposes an effective means of improving functional efficiency and operational stability. The advance of printable and functional materials utilized in additive manufacturing, coupled with the capability to produce bespoke geometries, has sparked great interest toward the 3-dimensional (3D) printing of immobilized enzymes. Printable biocatalysts represent a new generation of enzyme immobilization in a more customizable and adaptable manner, unleashing their potential functionalities for countless applications in industrial biotechnology. This review provides an overview of enzyme immobilization techniques and 3D printing technologies, followed by illustrations of the latest 3D printed enzyme-immobilized industrial and clinical applications. The unique advantages of harnessing 3D printing as an enzyme immobilization technique will be presented, alongside a discussion on its potential limitations. Finally, the future perspectives of integrating 3D printing with enzyme immobilization will be considered, highlighting the endless possibilities that are achievable in both research and industry.

Production and Purification of Candidate Subunit Vaccines by IC-Tagging Protein Encapsulation.

Particulate material is more efficient in eliciting immune responses. Here we describe the production of micro- and nanospheres formed by protein muNS-Mi from avian reoviruses, loaded with foreign epitopes for their use as vaccines.

A customizable 3D printed device for enzymatic removal of drugs in water.

The infiltration of drugs into water is a key global issue, with pharmaceuticals being detected in all nearly aqueous systems at often alarming concentrations. Pharmaceutical contamination of environmental water supplies has been shown to negatively impact ecological equilibrium and pose a risk to human health. In this study, we design and develop a novel system for the removal of drugs from water, termed as Printzyme. The device, fabricated with stereolithography (SLA) 3D printing, immobilises laccase sourced from Trametes Versicolor within a poly(ethylene glycol) diacrylate hydrogel. We show that SLA printing is a sustainable method for enzyme entrapment under mild conditions, and measure the stability of the system when exposed to extremes of pH and temperature in comparison to free laccase. When tested for its drug removal capacity, the 3D printed device substantially degraded two dissolved drugs on the European water pollution watch list. When configured in the shape of a torus, the device effectively removed 95% of diclofenac and ethinylestradiol from aqueous solution within 24 and 2 h, respectively, more efficiently than free enzyme. Being customizable and reusable, these 3D printed devices could help to efficiently tackle the world's water pollution crisis, in a flexible, easily scalable, and cost-efficient manner.

Chemical and thermal stabilization of CotA laccase via a novel one-step expression and immobilization in muNS-Mi nanospheres.

A methodology that programs eukaryotic or bacterial cells to encapsulate proteins of any kind inside micro/nanospheres formed by muNS-Mi viral protein was developed in our laboratory. In the present study such "in cellulo" encapsulation technology is utilized for immobilizing a protein with an enzymatic activity of industrial interest, CotA laccase. The encapsulation facilitates its purification, resulting in a cost-effective, one-step way of producing immobilized enzymes for industrial use. In addition to the ability to be recycled without activity loss, the encapsulated protein showed an increased pH working range and high resistance to chemical inactivation. Also, its activity was almost unaffected after 30 min incubation at 90 °C and 15 min at the almost-boiling temperature of 95 °C. Furthermore, the encapsulated laccase was able to efficiently decolorate the recalcitrant dye RB19 at room temperature.