The most important things you need to know about AlternativesToGd. More information about the separate Work Packages is available here. More information about the consortium and each partner can be found here.

Facts and Figures

Acronym: AlternativesToGd

Start date: October 1st, 2019

Duration: 36 months

End date: September 30th, 2022

Project coordinator: Prof. Rachel Katz-Brull, HMO

Consortium: 10 partners from 6 countries

Total funding: €3,065,956.25

Project Context

Recently, the European Medicines Agency (EMA) issued a recommendation to suspend three widely used magnetic resonance imaging contrast agents that are Gadolinium (Gd)-bearing, and the U.S. Food & Drug Administration (FDA) has required new class warnings for these agents.

This decision, although in the absence of clinical evidence, relates to potential major health concerns resulting from long-term accumulation of Gd in the patients’ bodies. New findings are coming out on an almost weekly basis reporting traces of Gd left in human tissues after repeated contrast-agent enhanced MRI. This sends a clear message to carefully consider the necessity of each contrast injection in individuals undergoing an MRI scan.

However, for a number of diagnostic procedures such as tumour characterisation, the use of a contrast agent is often essential. Although not all Gd-bearing contrast agents are banned by the EMA and the FDA, severe concerns about their long-term safety remain. The accumulation of Gd in different organs, including the brain, and Gd-related diseases requires the scientific community to seek radically new alternatives.

Objectives

Our vision is to identify and validate radically new compounds and technologies as alternatives to Gd-bearing contrast agents.

The new compounds and technologies will be tested in animal models of disease and the most promising ones will be selected for further clinical development. These new compounds should radically impact the field and will likely leading to a paradigm shift in MR-based diagnosis.

The new class of MRI contrast agents we’re developing will be metal-free, safe, and can completely eliminated from the human body after the MRI exam.

The agents will consist of small endogenous molecules, in which nuclear spins will be hyperpolarised to ensure high sensitivity to MR detection even at very low doses. These agents will be labelled with stable-isotopes and thus avoid any ionising radiation that is associated with nuclear medicine methods.

The new agents will be of small molecular weight, inert, and with a bio-distribution pattern similar to Gd-bearing contrast agents, i.e. predominantly in the vascular and extracellular spaces.

Our ultimate goal is to demonstrate the feasibility of replacing Gd-bearing contrast agents with a metal-free approach in at least one type of contrast-enhanced MRI examination – with the motivation to stimulate further research and development in academia and industry.

Project Output and Deliverables

The main objective is to develop, identify, and select the most promising approach for producing hyperpolarised contrast agents and administration routes that will provide an alternative to the conventional Gd-bearing contrast agents for contrast-enhanced MRI.

The specific aims of AlternativesToGd are:

  • Development of unique hyperpolarised agents via dissolution-dynamic nuclear polarisation (dDNP) and administration routes that produce long lasting and intense signal in the blood pool
  • Development of hyperpolarised small-molecules for biomedical imaging using parahydrogen-induced hyperpolarisation (PHIP)
  • Development of hyperpolarisation techniques based on optical or DNP irradiation of nano-diamonds
  • Development of tailored MRI tools for optimal observation of the hyperpolarised agents in vivo

Although the project aims at finding at least one replacement for the currently used Gd-bearing contrast agents, the variety of systems that will be developed may open the route for innovative diagnostic procedures based on the administration of “cocktail” made by two or more hyperpolarised molecules. The particular combination of decay times and bio-distribution properties may provide, in one shot, an in-depth characterisation of the tissue microenvironments that could be largely superior to what is currently achieved with the available contrast agents.

Impact

The use of hyperpolarised agents for perfusion imaging or tissue-retention imaging for diagnostic MRI is a new technology that does not exist today. We will lay the foundation for such a technology by providing the contrast agents, the means to increase their MR signal, and the routes for MR imaging of these hyperpolarised signals on clinical MRI scanners. There is also a potential for future social or economic impact and market creation. Society will gain by having access to medical imaging that does not leave potentially toxic deposits in the bodies of children and adults undergoing MRI examinations. Our results also have the potential to access new markets for medical imaging and contrast media companies, whether established or young start-ups.