Project description

Carbon monoxide (CO) has a very powerful anti-inflammatory effect and it specifically acts upon a number of cellular and molecular mechanisms that are involved in the RA disease process. Examples of these actions include the inhibition of the pro-inflammatory cytokines TNF, IL-1 and IL-6, the enhancement of the anti-inflammatory cytokine IL-10, the inhibition of leukocyte extravasation and mast cell activation, the down-regulation of T cell responses and the inhibition of apoptosis. All these effects have been published in respected peer-reviewed journals by distinguished research groups around the World (including from Harvard University, Columbia University, the University of Pittsburgh, the Northwick Park Institute for Medical Research in the UK and the Gulbenkian Institute of Science in Portugal).
On the other hand, the administration of CO as a gas to RA patients would be impractical and not effective, especially in light of the affinity with which CO binds to haemoglobin and of the difficulties involved in repeated administration of a gaseous treatment to patients with a chronic disease.

CO-releasing molecules (CORMs) promise to harvest the therapeutic potential of CO by delivering it in a more controlled fashion. In particular, Alfama's CORMs are small molecules, some of which release CO only or preferentially in chemical environments that are typical of an inflamed site. In addition, some CORMs can be administered orally, and most of them can be chemically modified to have better pharmacological properties without losing their CO releasing ability.

The main goal of this project is: to select a small number of exceptionally promising CORMs for the treatment of RA, to use adequate formulations for those compounds, to test their efficacy, toxicological profile and some detailed pharmacological properties, and ultimately arrive at one lead candidate for clinical development.

With this aim, the three participating SMEs, Alfama, Frimorfo and Micron will join their resources, critical mass and knowledge in the field of CORMs, pharmacological test, analysis, standardization and validation of biological assays to gain the ambitious but reasonable goal: at least one new molecule very close to clinical trials.

Although there is currently no cure for rheumatoid arthritis, several types of drugs are prescribed for this disease. These include steroids, non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs).
While steroids produce serious and dangerous side effects and are typically prescribed only in special situations, NSAIDs tend to mitigate pain and other symptoms without effectively reversing the disease course. Even more sophisticated NSAIDs like selective COX-2 inhibitors (Vioxx, Celebrex, and others) have recently been proven to cause cardiovascular problems.
DMARDs have limited efficacy and are associated with serious side effects. Biological DMARDs are commonly considered the most advanced type of drug prescribed for RA; they effectively halt disease progression by acting upon specific targets such as the pro-inflammatory cytokines TNF╬▒ and IL-1. However, biological DMARDs are extremely expensive due to the complexity of their development and manufacture, and their long-term use has been linked to serious problems including susceptibility to opportunistic infections and tumour formation.
Compounds currently in the clinical stages of development promise improvements over marketed drugs but will not completely solve the general issues. There is thus a great need for effective, harmless and affordable drugs that treat RA. CORMs hold the promise to become exactly that.

The different work units of the project are:

  • Chemical synthesis of CORMs (in gram-scale) to be tested; synthesis of structurally optimized molecules on the basis of SARs (Structure-Activity Relationships) derived from the biological tests; CORMs Formulations (Alfama)
  • Chemical testing (stability, CO release kinetics, solubility) (Alfama, Frimorfo, SBQ, Micron)
  • In vitro toxicity and preliminary efficacy (Alfama, UNICT)
  • In vivo acute toxicity (UNICT, Alfama)
  • In vivo inflammation and rheumatoid arthritis models (UNICT, IMM)
  • Effect on human tissue samples (IMM)
  • Histological, biochemical and haematological analyses (Frimorfo, SBQ)
  • Advanced formulations (Alfama)
  • Validation of efficacy, pharmacological parameters, bioavailability (Frimorfo, SBQ, Micron)
  • GMP manufacturing
  • Submission of IND application and preparation and performance of clinical trials (post-project) (Alfama)

For the participating SMEs which hold the intellectual property and major knowledge on CORMs and on specific drug development technologies, this will be a unique opportunity to sharply increase their value, by directly contributing for the placement of the first molecule of this kind in clinical testing.
The prospects of success are significant, due to the massive investment of critical mass and money in focused and planned Research and Technological Development activities.