LysoSENS research currently targets an early precursor of atherosclerosis, the leading cause of cardiovascular disease and stroke, the country's leading and third greatest killers. It kills more Americans each year than all cancers combined
Atherosclerosis is a cumulative, chronic disease whose precursors first appear in adolescence. Being a basic by-product of necessary metabolic processes, all adults have atherosclerotic plaques, to some extent. Normally, this accumulation is benign, but with time it manifests itself with chronic and cumulative tissue death in various organs by blocking blood flow. Such blockage becomes most seriously symptomatic in the case of the brain and heart.
The demonstrated culprit is called 7-ketocholesterol (7KC). The particular lysosomes accumulating this molecule live in phagocytes in the inner lining of artery walls. Phagocytes are cells which let in a greater variety of molecules than the average cell, since their role is to protect the body by absorbing and degrading harmful molecules. This is why other cells don't have the same problem with 7KC: they don't let it in in the first place.
Most molecules absorbed by lysosomes are decomposed by powerful enzymes and rereleased. There are, of course, macromolecules that our lysosomes can't degrade. Lysosomes try to do us a favor by containing such molecules, instead of rereleasing them. In the case of 7KC, this strategy slowly backfires. The lysosomes bloat from <5% of cell volume up to 80%, and create a cascade of arterial damage. Cholesterol from the blood, white blood cells, and other debris build up in the lesion. Cholesterol
therefore is both the cause and the effect of atherosclerosis, playing a role at both ends of pathogenesis. Calcification builds up around the unstable plaque, stiffening the artery, causing high blood pressure and making the heart work harder. Eventually plaques burst and clog blood flow elsewhere in the body. Tissue death, including stroke and congestive heart failure in the case of tissue of the brain and heart, results.
The lysosomes therefore need some help, some sort of enhancement, to enable them to degrade what they normally can't. LysoSENS's proposed approach is a modification of therapy used for lysosomal storage diseases, disorders in which lysosomes don't produce the full normal range of enzymes. The treatment is weekly or bi-weekly injection of the deficient enzyme. It is expected that in the case of 7KC, treatments
would be much less frequent, since 7KC builds up so slowly.
Fortunately, bacterial fungi exist in nature that degrade 7KC. The aim is therefore to modify their enzymes to maximize delivery to and efficacy in human lysosomes and minimize side effects. (In case it's unclear, nobody's talking about injecting bacteria, only the enzyme itself!) The search for such enzymes in nature started in early 2005. The advantage of finding them in nature first instead of engineering them from scratch is that nature has had hundreds of millions of years of practice to develop both
diversity of enzymes and effectiveness to degrade. Microbial organisms tend to have many enzymes for degrading the same stuff, but specialized for different situations (temperature, pH, etc.). This offers researchers more choice as to what is most effective in humans, what has the least toxicity, alternative enzymes if the best don't work for some people, etc.. Specialization also translates into reduced toxicity; ideally an enzyme will be active only once it's arrived in the low pH of the lysosome and nowhere else.
