Chief Scientific Officer, Sequenom, Inc.No slides available
Humans can only survive a few minutes without breathing oxygen. Oxygen is converted in the mitochondrial membrane to water and the energy liberated by this process helps power most bodily functions. Unfortunately, the conversion process occurs in several discrete steps and the intermediates in these steps are extremely toxic and damage (oxidize) the polyunsaturated fatty acids (PUFAs) required in mitochondrial membranes to give them the fluidity needed for proper function. The damaged PUFAs must be continually replaced, and because humans cannot make these PUFAs biosynthetically they have to be ingested in large quantities in the diet. In a young, healthy person the process of minimizing PUFA damage and replacement is adequate to repair damaged membranes but as people age, or in many age-related disease states, the PUFA damage exceeds the repair. As a result, the mitochondria and the cells that contain damaged PUFAs lose function and die.
Numerous attempts have been made to use antioxidants to reduce the production of damaged PUFAs. However these have not been effective enough to combat disease. This approach has been all but abandoned by the pharmaceutical industry, especially in their attempts to treat neurodegenerative diseases. An alternative therapeutic approach which is showing great promise in many different neurodegenerative indications is to replace 15-20% of the body’s natural PUFAs with deuterated derivatives (dPUFAs) which are much less readily oxidized, but otherwise retain and support all normal cellular functions. One compound known as RT001 is currently in clinical trials and has also been made available through an expanded access program for use in selected clinical indications, including those where increased PUFA oxidation drives disease processes. These studies show promise not just in potentially slowing the functional decline, normally seen in these indications, but also in providing initial evidence of functional restoration. The drug candidate RT001, appears to be safe and well tolerated at the dosages used and is predicted to achieve therapeutically efficacious exposure levels. Remarkably, humans and animals appear to treat RT001 like the normal nutrient: i) it appears to be distributed to the right places in the body; ii) it is metabolically modified as if the deuterium substitution were invisible; and iii) preclinical and clinical evidence indicates that oxidative damage is curtailed. We anticipate that if current clinical trends are reproduced in longer duration and larger studies it will become feasible to consider using these dPUFA materials to prevent the damage caused by a range of neurodegenerative diseases and thus eliminate one of the major challenges to cost effective health care.