LysoSENS at Rice University
Degradation of 7KC
Atherosclerosis, the cause of most age-related heart attacks and strokes, is thought to result from the accumulation of cholesterol and in particular toxic oxysterols in the arterial lining. The quantitatively, and possibly also qualitatively most important oxysterol is 7-ketocholesterol (7KC). Thus, 7KC is justly designated as the major target of medical bioremediation. So far, LysoSENS has focused on discovering microbial enzymes capable of degrading 7KC, and one such enzyme was found. In the meantime, other groups have characterized several further enzymes degrading 7KC in different ways.
None of the groups with 7KC degrading enzymes seem interested in applying their enzymes in a model of atherosclerosis (but the esterase groups do). Furthermore, there is no evidence of collaboration among any of the groups. Thus, it seems prudent for SENS Research Foundation to synthesize the individual efforts, prepare the application of all these enzymes in unified models of atherosclerosis, and evaluate them competitively and synergistically.
We have added N-glycosylation sites and lysosomal targeting tags to genes that code for five known 7KC degrading enzymes. When expressed in a yeast cell system, and targeted to the endoplasmic reticulum, these sites should receive oligomannose or paucimannose cores. This should generate appropriate localization in macrophages, giving them the ability to degrade 7KC.
In September 2012, a paper reporting results from the LysoSENS project that SENS Research Foundation funds at Rice University will be published in the printed edition of Biotechnology and Bioengineering. The research that produced these results was primarily performed by Dr. Jacques Mathieu in the lab of Dr. Pedro Alvarez, in Rice University’s Department of Environmental Engineering. The project has focused on identifying enzymes that can degrade or modify 7-ketocholesterol (7KC) in the lysosomal environment. Because the cytotoxic effects of 7KC on the lysosomes of macrophages and foam cells are a root cause of atherosclerosis, such enzymes could ultimately be used in vivo as a new class of regenerative therapies to prevent and reverse heart disease.
The paper, which we analyze in detail on SENS Research Foundation’s website here, is a significant advance in the science of LysoSENS. In previous studies, research funded by the Foundation has identified enzymes that can degrade 7KC in isolation from the cellular and lysosomal environment. The publication of this latest study marks the first time that an introduced microbial enzyme has been used inside living cells, and been shown to protect them against oxysterol-based cytotoxicity.
The success of the approach employed by the team at Rice makes this enzyme, Chromobacterium sp. DS1 cholesterol oxidase, an important step toward a true rejuvenation biotechnology -- a therapy that can target and repair damage that underlies the diseases and disabilities of the aging process. SENS Research Foundation is pleased to continue backing Dr. Mathieu's research, so that further work can move us closer to making such treatments a reality.