Clearance Therapeutics Against Lipofuscin (Rice University)

Clearance Therapeutics Against Lipofuscin

Principal Investigator: Pedro Alvarez

Research Team: Jason Gaspar, Jacques Mathieu

Many diseases of aging are driven in part by the accumulation of intracellular aggregates particular to specific cell types. For example, atherosclerotic lesions form when disabled, immobilized immune cells (macrophages) called foam cells adhere in the arterial wall after taking in 7-ketocholesterol (7-KC) and other damaged cholesterol byproducts in an effort to protect the arterial wall from their toxicity. Alzheimer’s and Parkinson’s are also, in part, lysosomal diseases. Additionally, many types of cells that rarely or never divide throughout adult life accumulate a more generic form of lysosomal waste known as lipofuscin, which impacts such critical cell types as neural, cardiac muscle, and skeletal muscle cells. Lipofuscin is hypothesized to derive largely from inadequate degradation of aged or dysfunctional mitochondria.
In 2014, the Rice University intracellular aggregate team developed a refined version of a previously-developed method that allows researchers to generate abundant lipofuscin in cells much more simply and in significantly less time (~5-10 days) than the earlier iteration. This method will enable researchers to understand lipofuscin metabolism and the ways that it deranges cells much more conveniently, and also test interventions designed to clear it out of cells. One of the ways that some lipids disable the lysosome in model foam cells is by lysosomal membrane permea- bilization (LMP) — a process that keeps lysosomes from maintaining the necessary acidity to properly degrade wastes, and that leads to the leakage of acids, enzymes, and toxic wastes into the cell. Looking into previous research, the Rice team noted a small molecule that has benefits in a rodent model of a human genetic lysosomal disease. In their own studies, the team found that this molecule is capable of rescuing LMP induced by exposure to certain damaged lipids.
This year, they found this same molecule is capable of reducing lipofuscin content their model of aged fibroblasts by roughly 30%, although it is not yet clear whether this is a true reduction in mature lipofuscin or is the result of more efficiently degrading its precursors. This latter result was unexpected, as lipofuscin is not predicted to be solubilized by the small molecule utilized. Nor is it likely that the small molecule is simply interfering with the Rice team’s system for generating lipofuscin in the cells. This opens up the possibility that the candidate drug is not merely helping the cell to export lipofuscin by making it more soluble, but is somehow contributing to the degradation of lipofuscin or to the rejuvenation of lysosomal function. The team is now testing several hypotheses for the mechanism, and is focused on how both aging and the small molecule may be affecting lysosome membrane content and function. After further exploration of the mechanism in their fibroblast model, the investigators would like to test drug efficacy in lipofuscin-laden heart cells (which are a more physiological model, albeit an expensive and difficult one with which to work) and eventually in aged mice.

Note: In September 2012, a paper reporting results from the LysoSENS project that SENS Research Foundation funds at Rice University was 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 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.