Guido Rasi

Nanopore Technology for Biomedical Applications

The ability to create well-defined and controlled interfaces has been an area of great interest over the last few years, particularly in the biomedical arena. This paper will describe the development of technology for the fabrication of nanopore membranes, and their operation in biological environments. With monodisperse pores sizes as small as 10 nanometers, these membranes offer advantages in their reproducibility, and their ability to be integrated with controlled biochemical surface modification protocols. A comprehensive review of results in the areas of nanopore and biocapsule microfabrication technologies, biocompatibility of nanomembrane materials, biologically appropriate post-processing protocols (bonding, sterilization), surface modification protocols, and appropriate mass transport models will be presented. The results point to the potential of using such technologies for therapeutic applications including immunoisolation biocapsules, drug delivery devices, and targeted biorecognition platforms.

From Adaptive Licensing to Adaptive Pathways: Delivering a Flexible Life-Span Approach to Bring New Drugs to Patients

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life‐span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade‐off, help de‐risk drug development, and lead to better outcomes for patients.

Open Clinical Trial Data for All? A View from Regulators

Hans-Georg Eichler from the European Medicines Agency and colleagues provide a view from regulators on access to clinical trial data.

Rhinitis and asthma in athletes: an ARIA document in collaboration with GA2LEN

This consensus document is aimed at reviewing evidence that the rhinits‐asthma links have peculiar features in athletes. Beside a review of epidemological data on the high prevalence of rhinitis and asthma in athletes, the effects on intense physical exercise on the immune system and repiratory functions are discussed, with special reference to the role of allergens and pollutants. In extending the Allergic Rhinitis and its Impact on Asthma (ARIA) recommendations to athletes, the issue is addressed of adapting diagnosis and management to criteria set by the International Olympic Committee (IOC) and regulations adopted by the World Anti‐Doping Agency (WADA).

Drug policy for an aging population--the European Medicines Agency's geriatric medicines strategy

At the European Medicines Agency, the aging of the population has prompted an analysis of whether the regulatory system is adapted to taking the needs of older people into account in the development, approval, and use of medications.

Microfabricated Biocapsules Provide Short-Term Immunoisolation of Insulinoma Xenografts

This study examines the viability and functionality of two insulinoma cell lines, RIN (1048) and βTC6F7, encapsulated within microfabricated biocapsules. Surface and bulk micromachining are integrated in the biocapsule fabrication process, resulting in a diffusion membrane with uniform pore size distribution as well as mechanical and chemical stability, surrounded by an anisotropically-etched silicon wafer, which serves as the encapsulation cavity. Insulinoma cells (4500 cells/biocapsule) were enclosed within these microfabricated biocapsules and subjected to a static incubation study after either implantation in BALB-C mice or incubation in vitro. Examination of retrieved microfabricated biocapsules revealed an insulin stimulatory index of approximately 1.5 for encapsulated RIN cells and 3.6 for encapsulated βTC6F7 cells for biocapsules with 18 nm pore sized microfabricated membranes, similar to indices of biocapsules incubated in vitro. There was an 80% decrease in cell stimulatory response between in vitro and in vivo 66 nm-biocapsules as compared to 20% for 18 nm-biocapsules, indicating that the immunoisolatory effectiveness depends greatly on achieving uniform pore sizes in the size range of 18 nm or smaller. The present study demonstrates the feasibility of using microfabricated biocapsules for the immunoisolation of insulinoma cells lines. The microfabricated biocapsule may serve as an alternative to conventional polymeric based biocapsules for possible use as in vivo insulin secreting bioreactor.

Thymosin alpha1: an endogenous regulator of inflammation, immunity, and tolerance.

Abstract:  Thymosin α1 (Tα1), first described and characterized by Allan Goldstein in 1972, is used worldwide for the treatment of some immunodeficiencies, malignancies, and infections. Although Tα1 has shown a variety of effects on cells and pathways of the immune system, its central role in modulating dendritic cell (DC) function has only recently been appreciated. As DCs have the ability to sense infection and tissue stress and to translate collectively this information into an appropriate immune response, an action on DCs would predict a central role for Tα1 in inducing different forms of immunity and tolerance. Recent results have shown that Tα1: (a) primed DCs for antifungal Th1 resistance through Toll‐like receptor (TLR)/MyD88‐dependent signaling and this translated in vivo in protection against aspergillosis; (b) activated plasmacytoid DCs (pDC) via the TLR9/MyD88‐dependent viral recognition, thus leading to the activation of interferon regulatory factor 7 and the promotion of the IFN‐α/IFN‐γ−dependent effector pathway, which resulted in vivo in protection against primary murine cytomegalovirus infection; (c) induced indoleamine 2,3‐dioxygenase activity in DCs, thus affecting tolerization toward self as well as microbial non‐self‐antigens, and this resulted in vivo in transplantation tolerance and protection from inflammatory allergy. Tα1 is produced in vivo by cleavage of prothymosin α in diverse mammalian tissues. Our data qualify Tα1 as an endogenous regulator of immune homeostasis and suggest that instructive immunotherapy with Tα1, via DCs and tryptophan catabolism, could be at work to control inflammation, immunity, and tolerance in a variety of clinical settings.

The risks of risk aversion in drug regulation

Drugs are approved by regulatory agencies on the basis of their assessment of whether the available evidence indicates that the benefits of the drug outweigh its risks. In recent years, regulatory agencies have been criticized both for being overly tolerant of risks or being excessively risk-averse, which reflects the challenge in determining an appropriate balance between benefit and risk with the limited data that is typically available before drug approval. The negative consequences of regulatory tolerance in allowing drugs onto the market that turn out to be unsafe are obvious, but the potential for adverse effects on public health owing to the absence of new drugs because of regulatory risk-aversion is less apparent. Here, we discuss the consequences of regulatory risk-aversion for public health and suggest what might be done to best align acceptance of risk and uncertainty by regulators with the interests of public health.

Thymosin alpha 1 in the treatment of cancer: from basic research to clinical application

Many studies have explored the effects of immunotherapy, alone or in combination with conventional therapies, on both experimental and human cancers. Evidence has been provided that combined treatments with thymosin alpha 1 (T alpha 1) and low doses of interferon (IFN) or interleukin (IL)-2 are highly effective in restoring several immune responses depressed by tumor growth and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to increase the anti-tumor effect of chemotherapy while markedly reducing the general toxicity of the treatment. The advantages of using this combined chemo-immunotherapeutic approach in experimental and human cancers are reviewed in this issue.

Access to patient-level trial data--a boon to drug developers

The European Medicines Agency aims to make patient-level data from clinical trials publicly accessible while protecting privacy; this would improve drug-development efficiency, cost-effectiveness, and comparative-effectiveness analysis and reduce duplication of effort.