Current therapies for MS are inadequate in that they reduce relapse rates in most cases, but do not fully halt disease progression. Furthermore, current therapies can have unwanted side-effects, and are administered by injection, a significant drawback for people with MS. In this project Associate Professor Flynn and his colleagues at Monash University will establish a proof-of-principle that demonstrates how orally administered therapies for MS can be developed in a manner that directly targets the immune cells responsible for MS, whilst sparing other tissues, including other types of immune cells.
The newly listed oral medication for MS, known as FTY720 or fingolimod, has provided the first oral alternative to the long-standing injectable immune-modifying therapies for MS. It has been shown to be effective, however, it is not without side-effects, having significant effects on the cardiovascular system and liver. These side-effects occur at the therapeutic doses of the drug and therefore limit the dose that can be delivered for therapeutic effect.
FTY720 targets a group of cellular signalling molecules that act through the S1P-receptor. There are five versions of the S1P molecule that have roles in a number of different biological systems in the body. However, it is has recently been shown that it is the S1P1 molecule that mediates both the immune effects and the cardiovascular effects. This means that it is not possible to design drugs that more specifically target only the immune system and not the cardiovascular system.
Consequently, Associate Professor Flynn and the team will take an approach of ‘directed exposure’ – selectively delivering the drug to the desired tissue, with the aim of improving the balance of therapeutic effect versus side-effects of this class of MS drugs.
The team will bring an exciting new approach to design new drugs that will be absorbed directly from the gastrointestinal system into the lymphatic system – where the target immune cells are found. This would greatly reduce the amount of drug that reaches the circulating blood system allowing the full therapeutic dose to be delivered to the lymphatic system without blood concentrations reaching the levels toxic to heart and liver. If successful, these principles may be extended to a number of other new and emerging drug classes for the treatment of MS and other autoimmune disorders.
The current project has successfully evaluated a new molecule that has very high absorption rates from the gastrointestinal tract into the lymphatic system in a laboratory model. It also has the desired effect of reducing white blood cell counts. This is a very exciting result. The team is now looking to see whether they can modify the molecule to retain its absorption into the lymphatic system but further improve its potency in immunomodulation. These excellent results will hopefully lead to improved therapies for people with MS in the future.
Updated: 13 June 2013
Updated: 03 January, 2011